TWI838626B - Lpa receptor antagonists and uses thereof - Google Patents
Lpa receptor antagonists and uses thereof Download PDFInfo
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- TWI838626B TWI838626B TW110117052A TW110117052A TWI838626B TW I838626 B TWI838626 B TW I838626B TW 110117052 A TW110117052 A TW 110117052A TW 110117052 A TW110117052 A TW 110117052A TW I838626 B TWI838626 B TW I838626B
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- alkyl
- pharmaceutically acceptable
- acceptable salt
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Abstract
Description
本發明係關於結合於溶血磷脂酸(LPA)受體(諸如LPAR1)且用作其之拮抗劑的化合物。本發明進一步係關於該等化合物用於治療及/或預防與一或多種LPA受體相關之疾病及/或病況,例如,LPAR1相關之疾病或病況的用途。The present invention relates to compounds that bind to lysophosphatidic acid (LPA) receptors, such as LPAR1, and act as antagonists thereof. The present invention further relates to the use of such compounds for the treatment and/or prevention of diseases and/or conditions associated with one or more LPA receptors, for example, diseases or conditions associated with LPAR1.
溶血磷脂酸(單-醯基-甘油-3-磷酸酯,LPA)為一類可以由溶血磷脂醯基膽鹼(LPC),例如藉由酶自分泌運動因子(autotaxin)產生的生物活性磷脂。典型的LPA具有甘油、sn-1位置處的酯連接之脂肪酸及sn-3位置處的磷酸酯頭部基團。已鑑別具有各種脂肪酸之LPA,包括軟脂醯基LPA (16:0)、硬脂醯基LPA (18:0)、油醯基LPA (18:1)、亞油醯基LPA (18:2)及二十碳四烯基(arachidonyl) LPA (20:4)。LPA經由類視紫質G蛋白偶聯受體(GPCR)家族發揮廣泛範圍之細胞反應,諸如增殖、分化、存活、遷移、黏附、侵襲及形態發生。六種LPA受體已經表徵且發現不同之處在於其組織分佈及下游傳訊路徑。此等六種LPA受體通常可互換地稱為LPAR1-6 (基因)或LPA1-6 (蛋白質)。LPA受體介導之傳訊已表明影響許多生物過程,諸如創傷癒合、免疫、癌發生、血管生成及神經生成。Lysophosphatidic acid (mono-acyl-glycerol-3-phosphate, LPA) is a class of biologically active phospholipids that can be produced from lysophosphatidylcholine (LPC), for example, by the enzyme autotaxin. A typical LPA has glycerol, an ester-linked fatty acid at the sn-1 position, and a phosphate head group at the sn-3 position. LPAs with various fatty acids have been identified, including oleyl LPA (16:0), stearyl LPA (18:0), oleyl LPA (18:1), linoleyl LPA (18:2), and arachidonyl LPA (20:4). LPA exerts a wide range of cellular responses such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis through the rhodopsin G protein-coupled receptor (GPCR) family. Six LPA receptors have been characterized and found to differ in their tissue distribution and downstream signaling pathways. These six LPA receptors are often referred to interchangeably as LPAR1-6 (gene) or LPA1-6 (protein). LPA receptor-mediated signaling has been shown to affect many biological processes such as wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis.
涉及LPA受體缺陷型小鼠或某些工具化合物之活體內研究已表明LPA受體作為各種疾病(包括癌症、纖維化、炎症、疼痛及心血管疾病)中之可能藥物目標的潛力。近年來,已在臨床上結合纖維變性疾病狀態(諸如特發性肺纖維化(IPF)及全身性硬化症)研究LPAR1拮抗劑。In vivo studies involving LPA receptor-deficient mice or certain tool compounds have demonstrated the potential of LPA receptors as possible drug targets in various diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease. In recent years, LPAR1 antagonists have been studied clinically in conjunction with fibrotic disease states, such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.
仍然需要具有期望選擇性、效能、代謝穩定性或降低之不利作用的LPA拮抗劑。There remains a need for LPA antagonists with desirable selectivity, potency, metabolic stability, or reduced adverse effects.
本發明提供適用作溶血磷脂酸受體1 (LPAR1)之抑制劑的化合物。本發明進一步係關於該等化合物用於經由藉由該等化合物結合LPAR1來治療及/或預防疾病及/或病況的用途。The present invention provides compounds useful as inhibitors of lysophosphatidic acid receptor 1 (LPAR1). The present invention further relates to the use of said compounds for treating and/or preventing diseases and/or conditions by binding to LPAR1 by said compounds.
在一個實施例中,本文提供一種式(I)化合物, 或其醫藥學上可接受之鹽, 其中: R1 為氫;C1-6 烷基;C2-6 烯基;C2-6 炔基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至10員雜芳基,其中各烷基、烯基、炔基、環烷基、雜環、芳基或雜芳基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫、C1-6 烷基或C3-6 環烷基, 其中各R1A 烷基、環烷基、雜環基、芳基及雜芳基視情況經1至4個相同或不同的R1C 取代,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基,且 其中各R1B1 、R1B2 及R1B3 烷基及各R1B1 、R1B2 及R1B3 環烷基視情況經1至3個鹵素取代;或 R1 為-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各C1-6 烷基或C3-6 環烷基視情況經1至4個相同或不同的R1E 取代,其中各R1E 獨立地選自鹵素;氰基;羥基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-O-R1F1 ;-N(R1F1 )(R1F2 );-C(O)N(R1F1 )(R1F2 );-NR1F1 C(O)R1F2 ;-S(O)0-2 R1F1 ;-S(O)2 N(R1F1 )(R1F2 )及-NR1F1 S(O)2 R1F2 ,其中各R1F1 及R1F2 獨立地為氫或C1-6 烷基,其中各R1E 烷基、環烷基、芳基及雜芳基視情況經1至3個相同或不同的R1G 取代,且其中各R1G 獨立地為C1-4 烷基、C1-4 烷氧基、羥基、鹵素或氰基; R2 為氫或視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C3-10 環烷基之相同或不同取代基取代的C1-6 烷基;或 R2 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C1-6 烷基之相同或不同取代基取代的C3-6 環烷基; 各R3 獨立地選自氘、鹵素、C1-6 烷基、C3-6 環烷基、-O-R2A1 及-N(R2A1 )(R2A2 ),其中該C1-6 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中各R2A1 及R2A2 獨立地為氫或視情況經1至3個相同或不同鹵素取代的C1-3 烷基; n為0、1、2、3或4; R4 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基、-C(O)N(R4A1 )及-N(R4A1 )(R4A2 )之相同或不同取代基取代的C1-6 烷基,其中各R4A1 及R4A2 獨立地為氫、C1-6 烷基或C3-10 環烷基;或 R4 為C3-6 環烷基或具有1或2個獨立地選自氮、氧及硫之雜原子的3至6員雜環基,其中該環烷基或雜環基視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基及C1-4 烷氧基之相同或不同取代基取代; X1 、X2 、X3 及X4 中之每一者獨立地選自CH及N; 各Y1 及Y2 獨立地為氫、氘,或視情況經1至3個獨立地選自氘、鹵素、氰基、C2-3 炔基、C1-4 烷氧基及-C(O)NH-(C1-4 H3-9 )之相同或不同取代基取代的C1-6 烷基;及 Z為C1-8 烷基;C1-6 烷氧基;C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該烷基、烷氧基、環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基、C1-4 烷氧基及C3-6 環烷基之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個選自C1-4 烷氧基及鹵素之相同或不同取代基取代;或 Y1 及Z連同其所連接之碳形成C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自氰基、C1-4 烷基、C1-4 烷氧基、C6-10 芳基及鹵素之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中該C6-10 芳基視情況經1至3個獨立地選自C1-4 烷基、C1-4 烷氧基及鹵素之相同或不同取代基取代,且Y2 為氫或氘。In one embodiment, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl; or a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen; cyano; nitro; pendoxy; C 1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 R 1B2 and R 1B3 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each R 1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 , R 1B2 and R 1B3 alkyl and each R 1B1 , R 1B2 and R 1B3 cycloalkyl are optionally substituted with 1 to 3 halogens; or R 1 is -OR 1D1 or -N(R 1D1 )(R 1D2 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted by 1 to 4 identical or different R 1E , wherein each R 1E is independently selected from halogen; cyano; hydroxyl; pendoxy; C 1-4 alkyl; C 3-10 cycloalkyl; 3 to 10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6 to 10 membered aryl; 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR 1F1 ; -N(R 1F1 )(R 1F2 ); -C(O)N(R 1F1 )(R 1F2 ); -NR 1F1 C(O)R 1F2 ; -S(O) 0-2 R 1F1 ; -S(O) 2 N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O) 2 R 1F2 , wherein each R 1F1 and R 1F2 are independently hydrogen or C 1-6 alkyl, wherein each R 1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R 1G , and wherein each R 1G is independently C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, halogen or cyano; R 2 is hydrogen or C 1-4 alkoxy substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 3-10 cycloalkyl; or R 2 is C 3-6 cycloalkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 1-6 alkyl; each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl , -OR 2A1 and -N(R 2A1 )(R 2A2 ), wherein the C 1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 are independently hydrogen or C 1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R R 4 is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ), wherein each R 4A1 and R 4A2 are independently hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl; or R 4 is C 3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy; X 1 , X 2 , X 3 and X each of Y1 and Y2 is independently selected from CH and N; each of Y1 and Y2 is independently hydrogen, deuterium, or C1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from deuterium , halogen, cyano, C2-3 alkynyl, C1-4 alkoxy and -C(O)NH-( C1-4H3-9 ); and Z is C1-8 alkyl; C1-6 alkoxy; C3-6 cycloalkyl; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl , alkoxy, cycloalkyl, aryl, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy and C 3-6 cycloalkyl, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 identical or different substituents selected from C 1-4 alkoxy and halogen; or Y 1 and Z together with the carbon to which they are attached form a C 3-6 cycloalkyl group; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from cyano, C 1-4 alkyl, C 1-4 alkoxy, C 6-10 aryl and halogen, wherein the C 1-4 alkyl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy and halogen, and Y 2 is hydrogen or deuterium.
在式I化合物或者其醫藥學上可接受之鹽的一些實施例中 R1 為氫;C1-6 烷基;C2-6 烯基;C2-6 炔基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至10員雜芳基,其中各烷基、烯基、炔基、環烷基、雜環、芳基或雜芳基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;- N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫或C1-6 烷基, 其中各R1A 烷基、環烷基、雜環基、芳基及雜芳基視情況經1至4個相同或不同的R1C 取代,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),且其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基;或 R1 為-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各C1-6 烷基或C3-6 環烷基視情況經1至4個相同或不同的R1E 取代,其中各R1E 獨立地選自鹵素;氰基;羥基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-O-R1F1 ;-N(R1F1 )(R1F2 );-C(O)N(R1F1 )(R1F2 );-NR1F1 C(O)R1F2 ;-S(O)0-2 R1F1 ;-S(O)2 N(R1F1 )(R1F2 )及-NR1F1 S(O)2 R1F2 ,其中各R1F1 及R1F2 獨立地為氫或C1-6 烷基,其中各R1E 烷基、環烷基、芳基及雜芳基視情況經1至3個相同或不同的R1G 取代,且其中各R1G 獨立地為C1-4 烷基、C1-4 烷氧基、羥基、鹵素或氰基; R2 為氫或視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C3-10 環烷基之相同或不同取代基取代的C1-6 烷基;或 R2 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C1-6 烷基之相同或不同取代基取代的C3-6 環烷基; 各R3 獨立地選自氘、鹵素、C1-6 烷基、C3-6 環烷基、-O-R2A1 及-N(R2A1 )(R2A2 ),其中該C1-6 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中各R2A1 及R2A2 獨立地為氫或視情況經1至3個相同或不同鹵素取代的C1-3 烷基; n為0、1、2、3或4; R4 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基、-C(O)N(R4A1 )及-N(R4A1 )(R4A2 )之相同或不同取代基取代的C1-6 烷基,其中各R4A1 及R4A2 獨立地為氫、C1-6 烷基或C3-10 環烷基;或 R4 為C3-6 環烷基或具有1或2個獨立地選自氮、氧及硫之雜原子的3至6員雜環基,其中該環烷基或雜環基視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基及C1-4 烷氧基之相同或不同取代基取代; X1 、X2 、X3 及X4 中之每一者獨立地選自CH及N; 各Y1 及Y2 獨立地為氫、氘,或視情況經1至3個獨立地選自氘、鹵素、氰基、C2-3 炔基、C1-4 烷氧基及-C(O)NH-(C1-4 H3-9 )之相同或不同取代基取代的C1-6 烷基;及 Z為C1-8 烷基;C1-6 烷氧基;C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該烷基、烷氧基、環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基、C1-4 烷氧基及C3-6 環烷基之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個選自C1-4 烷氧基及鹵素之相同或不同取代基取代;或 Y1 及Z連同其所連接之碳形成C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自氰基、C1-4 烷基、C1-4 烷氧基、C6-10 芳基及鹵素之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中該C6-10 芳基視情況經1至3個獨立地選自C1-4 烷基、C1-4 烷氧基及鹵素之相同或不同取代基取代,且Y2 為氫或氘。In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 is hydrogen; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-10 cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl; or 5-10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen; cyano; nitro; pendoxy; C 1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl, wherein each R 1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), and wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl; or R 1 is -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each C 1-6 alkyl or C 3-6 The 3-6 cycloalkyl group is optionally substituted by 1 to 4 identical or different R 1E groups , wherein each R 1E group is independently selected from halogen; cyano; hydroxyl; pendoxy; C 1-4 alkyl; C 3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR 1F1 ; -N(R 1F1 )(R 1F2 ); -C(O)N(R 1F1 )(R 1F2 ); -NR 1F1 C(O)R 1F2 ; -S(O) 0-2 R 1F1 ; -S(O) 2 N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O) 2 R 1F2 , wherein each R 1F1 and R 1F2 are independently hydrogen or C 1-6 alkyl, wherein each R 1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R 1G , and wherein each R 1G is independently C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, halogen or cyano; R 2 is hydrogen or C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 3-10 cycloalkyl; or R 2 is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 1-6 alkyl; each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), wherein the C 1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C 1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R 4 is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ) wherein each of R 4A1 and R 4A2 is independently hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl; or R 4 is C 3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy; each of X 1 , X 2 , X 3 and X 4 is independently selected from CH and N; each of Y 1 and Y 2 is independently hydrogen, deuterium, or optionally substituted with 1 to 3 identical or different substituents independently selected from deuterium, halogen, cyano, C 2-3 alkynyl, C 1-4 alkoxy; the alkyl radical being selected from the group consisting of -C(O)NH-(C 1-4 H 3-9 ) and -C 1-6 alkyl radical being substituted with the same or different substituents selected from -C(O)NH-(C 1-4 H 3-9 ); and Z is a C 1-8 alkyl radical ; a C 1-6 alkoxy radical; a C 3-6 cycloalkyl radical; a C 6-12 aryl radical; a 3- to 12-membered heterocyclic radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl radical, alkoxy radical, cycloalkyl radical, aryl radical, heterocyclic radical or heteroaryl radical is each optionally substituted with the same or different substituents selected independently from halogen, cyano, C 1-4 alkyl radical, C 1-4 alkoxy radical and C 3-6 cycloalkyl radical, wherein the C 1-4 alkyl radical is optionally substituted with 1 to 3 heteroatoms selected from C 6-12 or Y1 and Z together with the carbon to which they are attached form a C3-6 cycloalkyl group; a C6-12 aryl group; a 3-12 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-12 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 same or different substituents independently selected from cyano, C1-4 alkyl, C1-4 alkoxy, C6-10 aryl and halogen, wherein the C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from C1-4 alkoxy and halogen, and wherein the C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from C1-4 alkoxy and halogen, and wherein the C The 6-10 aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy and halogen, and Y 2 is hydrogen or deuterium.
在一些實施例中,本文提供醫藥組合物,其包含本文所提供之化合物或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑或載劑。在一些實施例中,該等醫藥組合物包含治療有效量之本文所提供之化合物或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑或載劑。In some embodiments, provided herein are pharmaceutical compositions comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
在一些實施例中,本文所提供之醫藥組合物進一步包含一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑或其醫藥學上可接受之鹽。在一些實施例中,該等醫藥組合物進一步包含治療有效量之一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑或其醫藥學上可接受之鹽。In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.
在一些實施例中,本發明提供抑制有需要之個體之LPAR1活性的方法,其包含向該個體投與治療有效量之本文所提供之化合物(例如,式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)之化合物)或其醫藥學上可接受之鹽,或本文所提供之醫藥組合物。In some embodiments, the present invention provides a method of inhibiting LPAR1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
在一些實施例中,本發明提供治療患有LPAR1介導之病況之患者的方法,其包含向該患者投與治療有效量之本文所提供之化合物(例如,式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)之化合物)或其醫藥學上可接受之鹽,或本文所提供之醫藥組合物。In some embodiments, the present invention provides a method for treating a patient suffering from an LPAR1-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
相關申請案之交互參照Cross-reference to related applications
本申請案主張在2020年6月3日提交的美國臨時申請案第63/034,220號及在2020年12月23日提交的美國臨時申請案第63/130,242號之35 U.S.C. § 119(e)下的權益,其出於所有目的特此以全文引用之方式併入本文中。This application claims the benefit of 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/034,220, filed on June 3, 2020, and U.S. Provisional Application No. 63/130,242, filed on December 23, 2020, which are hereby incorporated by reference in their entirety for all purposes.
本發明係關於LPA受體拮抗劑,諸如LPAR1之拮抗劑。本發明亦係關於與LPAR1拮抗劑相關之組合物及方法及此類化合物用於治療及/或預防LPAR1介導之疾病及病況之用途。本發明亦係關於治療及/或預防肝病之組合物及方法,包括LPAR1拮抗劑以及一或多種額外治療劑。The present invention relates to LPA receptor antagonists, such as antagonists of LPAR1. The present invention also relates to compositions and methods related to LPAR1 antagonists and the use of such compounds for treating and/or preventing LPAR1-mediated diseases and conditions. The present invention also relates to compositions and methods for treating and/or preventing liver disease, including LPAR1 antagonists and one or more additional therapeutic agents.
通常咸信,患有某些LPAR1介導之疾病,諸如癌症、纖維化、炎症、疼痛及心血管疾病或肝病(包括非酒精性脂肪肝病(NAFLD)及非酒精性脂肪變性肝炎(NASH))的患者可以得益於用LPAR1拮抗劑及視情況一或多種額外治療劑進行之治療。 定義及一般參數 It is generally believed that patients with certain LPAR1-mediated diseases, such as cancer, fibrosis, inflammation, pain, and cardiovascular disease or liver disease, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), may benefit from treatment with LPAR1 antagonists and, optionally, one or more additional therapeutic agents.
在本發明被視為所主張之標的物的範例且不意欲將所附申請專利範圍限於所說明之特定實施例的理解下進行以下描述。為方便起見,提供在本發明通篇中所使用之標題,且不認為該等標題以任何方式限制申請專利範圍。在任何標題下說明之實施例可與在任何其他標題下說明之實施例組合。The following description is made with the understanding that the present invention is considered an example of the claimed subject matter and is not intended to limit the scope of the appended patent application to the specific embodiments described. The headings used throughout the present invention are provided for convenience and are not to be considered to limit the scope of the patent application in any way. The embodiments described under any heading may be combined with the embodiments described under any other heading.
除非另外定義,否則本文中所使用之所有技術及科學術語均具有如一般熟習此項技術者通常所理解的相同含義。必須注意,除非文中另外清楚地指示,否則本文及所附申請專利範圍中所使用之單數形式「一(a/an)」及「該」包括複數個提及物。因此,例如對「化合物」之參考包括複數個此類化合物且對「分析法」之參考包括對一或多個分析法及熟習此項技術者已知的其等效物之參考等。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. It should be noted that the singular forms "a", "an" and "the" used herein and in the appended claims include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, etc.
如本說明書中所使用,以下術語及片語一般意欲具有如在下文中闡述之含義,除了其中使用該等術語及片語之上下文另外指示的情況。As used in this specification, the following terms and phrases are generally intended to have the meanings as set forth below, except where the context in which they are used indicates otherwise.
不在兩個字母或符號之間的短劃線(「-」)用於指示取代基之連接點。舉例而言,-CONH2 經由碳原子連接。在化學基團之前端或末端處之短劃線為出於方便之目的;可在具有或不具有一或多個短劃線之情況下描繪化學基團而不會丟失其普通含義。穿過結構中之線所繪製的波浪線指示基團之連接點。除非在化學上或在結構上需要,否則化學基團所書寫或命名之次序不指示或暗示方向性。出自環中心之實線指示環上之取代基之連接點可以處於任何環原子處。舉例而言,以下結構中之Ra 可以與五個碳環原子中之任一者連接,或Ra 可以置換與氮環原子連接之氫:。A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted with or without one or more dashes without losing its ordinary meaning. A wavy line drawn through the line in the structure indicates the point of attachment of the group. Unless required chemically or structurally, the order in which the chemical groups are written or named does not indicate or imply directionality. A solid line from the center of a ring indicates that the point of attachment of a substituent on the ring can be at any ring atom. For example, Ra in the following structure can be attached to any of the five carbon ring atoms, or Ra can replace a hydrogen attached to a nitrogen ring atom: .
前綴「Cu-v 」指示隨後的基團具有u至v個碳原子。舉例而言,「C1-6 烷基」指示該烷基具有1至6個碳原子。同樣,術語「x至y員」環(其中x及y為數值範圍,諸如「3至12員雜環基」)係指含有x-y個(例如,3-12個)原子之環,該等原子之至多80%可為諸如N、O、S、P之雜原子,且其餘原子為碳。The prefix " Cuv " indicates that the following group has u to v carbon atoms. For example, " C1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "x to y membered" ring (where x and y are numerical ranges, such as "3 to 12 membered heterocyclic group") refers to a ring containing xy (e.g., 3-12) atoms, up to 80% of which may be heteroatoms such as N, O, S, P, and the remaining atoms are carbon.
此外,可使用或可不使用某些常用替代性化學名稱。舉例而言,二價基團,諸如二價「烷基」、二價「芳基」等亦可分別稱為「伸烷基(alkylene)」或「伸烷基(alkylenyl)」或烷二基(alkylyl)、「伸芳基(arylene)」或「伸芳基(arylenyl)」或芳二基(arylyl)。In addition, some commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" and divalent "aryl" may also be referred to as "alkylene" or "alkylenyl" or alkylyl, "arylene" or "arylenyl" or arylyl, respectively.
「本文所揭示之化合物」或「本發明之化合物」或「本文所提供之化合物」或「本文所描述之化合物」係指式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)化合物。亦包括上文所提供之特定化合物1至338(例如實例1-92)。"Compounds disclosed herein" or "compounds of the present invention" or "compounds provided herein" or "compounds described herein" refer to compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi). Also included are specific compounds 1 to 338 provided above (e.g., Examples 1-92).
本文中,對「約」一個值或參數之提及包括(及描述)針對該值或參數本身之實施例。在某些實施例中,術語「約」包括指示量±10%。在其他實施例中,術語「約」包括指示量±5%。在某些其他實施例中,術語「約」包括指示量±1%。此外,術語「約X」包括「X」之描述。此外,除非上下文另外明確指示,否則單數形式「一(a)」及「該(the)」包括複數個參考物。因此,例如對「化合物」之參考包括複數個此類化合物且對「分析法」之參考包括對一或多個分析法及熟習此項技術者已知的其等效物之參考。Herein, references to "about" a value or parameter include (and describe) embodiments for the value or parameter itself. In certain embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In certain other embodiments, the term "about" includes an indicated amount ±1%. In addition, the term "about X" includes a description of "X". In addition, unless the context clearly indicates otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "analytical methods" includes reference to one or more analytical methods and their equivalents known to those skilled in the art.
「烷基」係指非分支鏈或分支鏈飽和烴鏈。如本文所使用,烷基具有1至20個碳原子(亦即,C1-20 烷基)、1至8個碳原子(亦即,C1-8 烷基)、1至6個碳原子(亦即,C1-6 烷基)、1至4個碳原子(亦即,C1-4 烷基)或1至3個碳原子(亦即,C1-3 烷基)。烷基之實例包括甲基、乙基、丙基、異丙基、正丁基、二級丁基、異丁基、三級丁基、戊基、2-戊基、異戊基、新戊基、己基、2-己基、3-己基及3-甲基戊基。當具有特定碳數之烷基藉由化學名稱命名或藉由分子式鑑別時,可涵蓋具有該碳數之所有位置異構體;因此,舉例而言,「丁基」包括正丁基(亦即,-(CH2 )3 CH3 )、二級丁基(亦即,-CH(CH3 )CH2 CH3 )、異丁基(亦即,-CH2 CH(CH3 )2 )及三級丁基(亦即,-C(CH3 )3 );且「丙基」包括正丙基(亦即,-(CH2 )2 CH3 )及異丙基(亦即,-CH(CH3 )2 )。"Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), or 1 to 3 carbon atoms (i.e., C1-3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl, isobutyl, tertiary butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a particular number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons are encompassed; thus, for example, "butyl" includes n-butyl (i.e., -( CH2 ) 3CH3 ), dibutyl (i.e., -CH( CH3 ) CH2CH3 ), isobutyl (i.e., -CH2CH ( CH3 ) 2 ), and tertiary butyl ( i.e. , -C( CH3 ) 3 ); and "propyl" includes n-propyl (i.e., -( CH2 ) 2CH3 ) and isopropyl (i.e., -CH( CH3 ) 2 ) .
「烯基」係指含有至少一個碳碳雙鍵且具有2至20個碳原子(亦即C2-20 烯基)、2至8個碳原子(亦即C2-8 烯基)、2至6個碳原子(亦即C2-6 烯基)或2至4個碳原子(亦即C2-4 烯基)之脂族基。烯基之實例包括乙烯基、丙烯基、丁二烯基(包括1,2-丁二烯基及1,3-丁二烯基)。"Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
「炔基」係指含有至少一個碳碳參鍵且具有2至20個碳原子(亦即C2-20 炔基)、2至8個碳原子(亦即C2-8 炔基)、2至6個碳原子(亦即C2-6 炔基)或2至4個碳原子(亦即C2-4 炔基)之脂族基。術語「炔基」亦包括具有一個參鍵及一個雙鍵之彼等基團。"Alkynyl" refers to an aliphatic group containing at least one carbon-carbon carbon bond and having 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes those groups having one carbon bond and one double bond.
「烷氧基」係指基團「烷基-O-」。烷氧基之實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、三級丁氧基、二級丁氧基、正戊氧基、正己氧基及1,2-二甲基丁氧基。"Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, di-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.
「醯基」係指基團-C(=O)R,其中R為氫、烷基、環烷基、雜環基、芳基、雜烷基或雜芳基;其中之每一者可視情況經取代,如本文所定義。醯基之實例包括甲醯基、乙醯基、環己基羰基、環己基甲基-羰基及苯甲醯基。"Acyl" refers to the radical -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclo, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
「胺基」係指基團-NRy Rz ,其中Ry 及Rz 獨立地選自由以下組成之群:氫、烷基、鹵烷基、芳基、雜芳基、環烷基或雜環基;其中之每一者可視情況經取代。"Aminyl" refers to the group -NRyRz , wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclo; each of which may be optionally substituted.
「芳基」係指包括稠合系統的具有單個環(例如單環)或多個環(例如雙環或三環)之芳族碳環基。如本文所使用,芳基具有6至20個環碳原子(亦即C6-20 芳基)、6至12個碳環原子(亦即C6-12 芳基),或6至10個碳環原子(亦即C6-10 芳基)。芳基之實例包括苯基、萘基、茀基及蒽基。然而,芳基不以任何方式涵蓋下文所定義之雜芳基或與其重疊。若一或多個芳基與雜芳基環稠合,則所得環系統為雜芳基。"Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl group.
「氰基」或「甲腈」係指基團-CN。"Cyano" or "carbonitrile" refers to the radical -CN.
「環烷基」係指具有單個環或多個環之包括稠合、橋接及螺環系統的飽和或部分飽和環烷基。術語「環烷基」包括環烯基(亦即,具有至少一個雙鍵之環狀基團)。如本文中所使用,環烷基具有3至20個環碳原子(亦即C3-20 環烷基)、3至12個環碳原子(亦即C3-12 環烷基)、3至10個環碳原子(亦即C3-10 環烷基)、3至8個環碳原子(亦即C3-8 環烷基)或3至6個環碳原子(亦即C3-6 環烷基)。環烷基之實例包括環丙基、環丁基、環戊基及環己基。"Cycloalkyl" refers to saturated or partially saturated cycloalkyl groups having a single ring or multiple rings, including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl groups), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl groups), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl groups), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl groups), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl groups). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
「稠合」係指環結合於相鄰環。在一些實施例中,稠環系統為雜環基。在一些實施例中,稠環系統為氧雜雙環己烷基。在一些實施例中,稠環系統為。"Fused" means that the ring is bonded to an adjacent ring. In some embodiments, the fused ring system is a heterocyclic ring. In some embodiments, the fused ring system is an oxahertabicyclohexane. In some embodiments, the fused ring system is .
「橋接」係指其中環上之非相鄰原子藉由二價取代基(諸如伸烷基、含有一個或兩個雜原子之伸烷基)或單個雜原子接合之環稠合。奎寧環基及金剛烷基為橋接環系統之實例。在一些實施例中,橋接環係二環戊基(雙環[1.1.1]戊基])或雙環辛基(雙環[2.2.2]辛基)。在一些實施例中,橋環為 。"Bridged" refers to a ring fusion in which non-adjacent atoms on the ring are joined by a divalent substituent (e.g., alkylene, alkylene containing one or two heteroatoms) or a single heteroatom. Quininyl and adamantyl are examples of bridged ring systems. In some embodiments, the bridged ring is dicyclopentyl (bicyclo[1.1.1]pentyl]) or bicyclooctyl (bicyclo[2.2.2]octyl). In some embodiments, the bridged ring is .
「螺」係指藉由相同碳原子處之兩個鍵接合的環取代基。螺基之實例包括1,1-二乙基環戊烷、二甲基-二氧雜環戊烷及4-苯甲基-4-甲基哌啶,其中該環戊烷及哌啶分別為螺取代基。在一些實施例中,螺取代基為螺戊基(螺[a.b]戊基)、螺己烯基、螺庚烷基或螺癸基。在一些實施例中,螺取代基為 。"Spiro" refers to a cyclo substituent joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxacyclopentane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine are spiro substituents, respectively. In some embodiments, the spiro substituent is spiropentyl (spiro[ab]pentyl), spirohexenyl, spiroheptyl, or spirodecanyl. In some embodiments, the spiro substituent is .
「鹵素」或「鹵基」包括氟、氯、溴及碘。"Halogen" or "halogen group" includes fluorine, chlorine, bromine and iodine.
「雜芳基」係指具有單個環、多個環或多個稠環之芳族基,其中一或多個環雜原子獨立地選自氮、氧及硫。如本文所使用,雜芳基包括1至20個碳環原子(亦即,C1-20 雜芳基)、3至12個碳環原子(亦即,C3-12 雜芳基)或3至8碳環原子(亦即,C3-8 雜芳基);及獨立地選自氮、氧及硫之1至5個環雜原子、1至4個環雜原子、1至3個環雜原子、1至2個環雜原子或1個環雜原子。雜芳基之實例包括嘧啶基、嘌呤基、吡啶基、嗒𠯤基、苯并噻唑基及吡唑基。雜芳基不涵蓋如上文所定義之芳基或與其重疊。"Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more heteroaryl atoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C1-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroaryl atoms, 1 to 4 heteroaryl atoms, 1 to 3 heteroaryl atoms, 1 to 2 heteroaryl atoms, or 1 heteroaryl atom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridinyl, benzothiazolyl and pyrazolyl. Heteroaryl groups do not include aryl groups as defined above or overlap with them.
「雜環基」或「雜環(heterocyclic ring/heterocycle)」係指具有一或多個獨立地選自氮、氧及硫之環雜原子的非芳族環烷基。如本文所使用,除非另外指示,否則「雜環基」或「雜環(heterocyclic ring/heterocycle)」係指飽和或部分飽和環,例如在一些實施例中,「雜環基」或「雜環(heterocyclic ring/heterocycle)」係指在具體情況下部分飽和之環。術語「雜環基」或「雜環(heterocyclic ring/heterocycle)」包括雜環烯基(亦即具有至少一個雙鍵之雜環基)。雜環基可為單個環或多個環,其中多個環可經稠合、橋接或螺接。如本文所使用,雜環基具有2至20個碳環原子(亦即C2-20 雜環基)、2至12個碳環原子(亦即C2-12 雜環基)、2至10個碳環原子(亦即C2-10 雜環基)、2至8個碳環原子(亦即C2-8 雜環基)、3至12個碳環原子(亦即C3-12 雜環基)、3至8個碳環原子(亦即C3-8 雜環基)或3至6個碳環原子(亦即C3-6 雜環基);具有獨立地選自氮、硫或氧之1至5個環雜原子、1至4個環雜原子、1至3個環雜原子、1至2個環雜原子或1個環雜原子。雜環基之實例包括吡咯啶基、哌啶基、哌𠯤基、氧呾基(oxetanyl)、二氧戊環基、吖呾基及𠰌啉基。如本文所使用之術語「雜環(heterocycle/heterocyclic ring)」及「雜環基(heterocyclyl)」可互換使用。"Heterocyclic" or "heterocyclic ring/heterocycle" refers to a non-aromatic cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, unless otherwise indicated, "heterocyclic" or "heterocyclic ring/heterocycle" refers to a saturated or partially saturated ring, for example, in some embodiments, "heterocyclic" or "heterocyclic ring/heterocycle" refers to a partially saturated ring in a specific instance. The term "heterocyclic" or "heterocyclic ring/heterocycle" includes heterocycloalkenyl (i.e., a heterocyclic group having at least one double bond). A heterocyclic group may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged or spiro-connected. As used herein, a heterocyclic group has 2 to 20 carbon ring atoms (i.e., C2-20 heterocyclic group), 2 to 12 carbon ring atoms (i.e., C2-12 heterocyclic group), 2 to 10 carbon ring atoms (i.e., C2-10 heterocyclic group), 2 to 8 carbon ring atoms (i.e., C2-8 heterocyclic group), 3 to 12 carbon ring atoms (i.e., C3-12 heterocyclic group), 3 to 8 carbon ring atoms (i.e., C3-8 heterocyclic group) or 3 to 6 carbon ring atoms (i.e., C 3-6 heterocyclic ring); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatoms independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperonyl, oxetanyl, dioxolanyl, azanyl and linolyl. As used herein, the terms "heterocycle" and "heterocyclic ring" and "heterocyclyl" are used interchangeably.
「羥基(Hydroxy/hydroxyl)」係指基團-OH。"Hydroxy" or "hydroxyl" refers to the group -OH.
「側氧基」係指基團(=O)或(O)。"Oxy" refers to the group (=O) or (O).
「磺醯基」係指基團-S(O)2 Rc ,其中Rc 為烷基、雜環基、環烷基、雜芳基或芳基。磺醯基之實例為甲基磺醯基、乙基磺醯基、苯磺醯基及甲苯磺醯基。"Sulfonyl" refers to the radical -S(O) 2Rc , wherein Rc is alkyl, heterocyclic, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.
除非另外指示,否則每當基團之圖形表示以單鍵結氮原子結束時,彼基團表示-NH2 基團。類似地,除非以其他方式表述,否則考慮到熟習此項技術者之知識,意味且認為在必要時存在氫原子以使價數完整或提供穩定性。Unless otherwise indicated, whenever a graphic representation of a group terminates in a single bond to a nitrogen atom, that group represents a -NH 2 group. Similarly, unless otherwise indicated, the presence of hydrogen atoms where necessary to complete the valence or provide stability is meant and assumed, taking into account the knowledge of those skilled in the art.
術語「視情況選用之」或「視情況」意謂隨後所描述之事件或情形可發生或可不發生,且該描述包括其中該事件或情形發生之情況及其中該事件或情形不發生之情況。此外,術語「視情況經取代之」意謂指定原子或基團上之任一或多個氫原子可經或可不經除氫以外之部分置換。The term "optionally" or "as the case may be" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. In addition, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced with a moiety other than hydrogen.
術語「經取代」意謂所指定原子或基團上之任何一或多個氫原子經除氫以外之一或多個取代基置換,其限制條件為不超過所指定原子之正常價數。一或多個取代基包括(但不限於)烷基、烯基、炔基、烷氧基、醯基、胺基、醯胺基、甲脒基、芳基、疊氮基、胺甲醯基、羧基、羧基酯、氰基、胍基、鹵基、鹵烷基、鹵烷氧基、雜烷基、雜芳基、雜環基、羥基、肼基、亞胺基、側氧基、硝基、烷基亞磺醯基、磺酸、烷基磺醯基、硫氰酸酯、硫醇、硫酮或其組合。藉由用無限地附加之其他取代基(例如,具有經取代之烷基之經取代之芳基,該經取代之烷基本身由經取代之芳基取代,該經取代之芳基進一步由經取代之雜烷基取代等等)定義取代基所獲得之聚合物或類似的無限結構並不意欲包括在本文中。除非另外指出,否則本文所描述之化合物中的連續置換之最大數目為三。舉例而言,用兩個其他經取代之芳基連續取代經取代之芳基限於經(經(經取代之芳基)取代之芳基)取代之芳基。類似地,以上定義不意欲包括不允許之取代模式(例如,經5個氟取代之甲基或具有兩個相鄰氧環原子之雜芳基)。此類不允許之取代模式為熟習此項技術者所熟知的。當用於修飾化學基團時,術語「經取代」可描述本文所定義之其他化學基團。舉例而言,術語「經取代之芳基」包括(但不限於) 「烷基芳基」。除非另外規定,否則在基團描述為視情況經取代之情況下,該基團之任何取代基本身未經取代。The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced by one or more substituents other than hydrogen, with the proviso that the normal valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amine, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halogen, halogenalkyl, halogenoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, pendoxy, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or a combination thereof. Polymers or similar infinite structures obtained by defining substituents with unlimited additional substituents (e.g., substituted aryl with substituted alkyl, which is itself substituted by substituted aryl, which is further substituted by substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise indicated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl with two other substituted aryls is limited to aryl substituted with (aryl substituted with (substituted aryl)). Similarly, the above definition is not intended to include disallowed substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless otherwise specified, where a group is described as optionally substituted, any substituent of that group is itself unsubstituted.
在一些實施例中,術語「經取代之烷基」係指具有包括羥基、鹵基、胺基、烷氧基、環烷基、雜環基、芳基及雜芳基之一或多個取代基之烷基。在額外實施例中,「經取代之環烷基」係指具有一或多個包括烷基、鹵烷基、環烷基、雜環基、芳基、雜芳基、胺基、烷氧基、鹵基、側氧基及羥基之取代基的環烷基;「經取代之雜環基」係指具有一或多個包括烷基、胺基、鹵烷基、雜環基、環烷基、芳基、雜芳基、烷氧基、鹵基、側氧基及羥基之取代基的雜環基;「經取代之芳基」係指具有一或多個包括鹵基、烷基、胺基、鹵烷基、環烷基、雜環基、雜芳基、烷氧基及氰基之取代基的芳基;「經取代之雜芳基」係指具有一或多個包括鹵基、胺基、烷基、鹵烷基、環烷基、芳基、雜環基、雜芳基、烷氧基及氰基之取代基的雜芳基;且「經取代之磺醯基」係指基團-S(O)2 R,其中R經一或多個包括烷基、環烷基、雜環基、芳基及雜芳基之取代基取代。在其他實施例中,該一或多個取代基可進一步經鹵基、烷基、鹵烷基、羥基、烷氧基、環烷基、雜環基、芳基或雜芳基取代,其中之每一者均經取代。在其他實施例中,取代基可進一步經鹵基、烷基、鹵烷基、烷氧基、羥基、環烷基、雜環基、芳基或雜芳基取代,其中之各者均未經取代。In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halogen, amino, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, halogen, cycloalkyl, heterocyclic, aryl, heteroaryl, amino, alkoxy, halogen, pendoxy, and hydroxyl; "substituted heterocyclic" refers to a heterocyclic group having one or more substituents including alkyl, amino, halogen, heterocyclic, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, pendoxy, and hydroxyl. ; "substituted aryl" refers to aryl having one or more substituents including halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, alkoxy and cyano; "substituted heteroaryl" refers to heteroaryl having one or more substituents including halogen, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkoxy and cyano; and "substituted sulfonyl" refers to the group -S(O) 2R , wherein R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which is unsubstituted.
在一些實施例中,經取代之環烷基、經取代之雜環基、經取代之芳基及/或經取代之雜芳基包括具有在環原子上之取代基的環烷基、雜環基、芳基及/或雜芳基,在環原子上之取代基使環烷基、雜環基、芳基及/或雜芳基與化合物之其餘部分連接。舉例而言,在以下部分中,環丙基經甲基取代:。In some embodiments, substituted cycloalkyl, substituted heterocyclo, substituted aryl and/or substituted heteroaryl include cycloalkyl, heterocyclo, aryl and/or heteroaryl groups having substituents on the ring atoms that connect the cycloalkyl, heterocyclo, aryl and/or heteroaryl group to the rest of the compound. For example, in the following moiety, the cyclopropyl group is substituted with a methyl group: .
本文中經說明性描述之揭示內容可在無本文中未特定揭示之任何一或多個元件、一或多個限制的情況下予以適當實踐。因此,舉例而言,應當廣泛地且非限制性地理解術語「包含」、「包括」、「含有」等。此外,所採用之術語及表達用作描述而非限制之術語,且在使用此類術語及表達中不意欲排除所展示及描述之特徵的任何等效物或其部分,但應認識到,在本發明所主張之範疇內,各種修改係可能的。The disclosure illustratively described herein may be properly practiced without any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. should be understood broadly and non-restrictively. Furthermore, the terms and expressions employed are used as terms of description rather than limitation, and in the use of such terms and expressions, no equivalents or portions thereof of the features shown and described are intended to be excluded, but it should be recognized that various modifications are possible within the scope of the invention.
本發明之化合物可以呈醫藥學上可接受之鹽的形式。術語「醫藥學上可接受之鹽」係指由醫藥學上可接受之無毒鹼或酸(包括無機鹼或酸及有機鹼或酸)製備的鹽。本發明之化合物可以呈醫藥學上可接受之鹽的形式。術語「醫藥學上可接受之鹽」係指由醫藥學上可接受之無毒鹼或酸(包括無機鹼或酸及有機鹼或酸)製備的鹽。倘若本發明之化合物含有一或多種酸基或鹼基,則本發明亦包含其對應醫藥學上或毒理學上可接受之鹽,特定言之,其醫藥學上可利用之鹽。因此,含有酸基之本發明之化合物可以存在於此等基團上,且可以根據本發明例如用作鹼金屬鹽、鹼土金屬鹽或銨鹽。此類鹽之更精確實例包括鈉鹽、鉀鹽、鈣鹽、鎂鹽,或具有氨或諸如(例如)乙胺、乙醇胺、三乙醇胺、胺基酸之有機胺或熟習此項技術者所已知之其他鹼的鹽。含有一或多個鹼基(亦即可以經質子化之基團)的本發明之化合物可以存在,且可根據本發明以其與無機酸或有機酸之加成鹽的形式予以使用。適合的酸之實例包括氯化氫、溴化氫、磷酸、硫酸、硝酸、甲磺酸、對甲苯磺酸、萘二硫酸、草酸、乙酸、酒石酸、乳酸、柳酸、苯甲酸、甲酸、丙酸、特戊酸、二乙基乙酸、丙二酸、丁二酸、庚二酸、反丁烯二酸、順丁烯二酸、蘋果酸、胺基硫酸、苯基丙酸、葡萄糖酸、抗壞血酸、異煙酸、檸檬酸、己二酸,及熟習此項技術者已知之其他酸。The compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or acids and organic bases or acids). The compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or acids and organic bases or acids). If the compounds of the present invention contain one or more acid groups or alkaline groups, the present invention also includes the corresponding pharmaceutically or toxicologically acceptable salts, specifically, their pharmaceutically usable salts. Thus, compounds according to the invention containing acid groups may be present on these groups and may be used according to the invention, for example, as alkaline metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine, amino acids or other bases known to those skilled in the art. Compounds according to the invention containing one or more alkaline groups (i.e. groups that can be protonated) may be present and may be used according to the invention in the form of addition salts thereof with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfuric acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, apple acid, aminosulfuric acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and others known to those skilled in the art.
若本發明之化合物在分子中同時含有酸基及鹼基,則本發明除所提及之鹽形式以外亦包括內鹽或甜菜鹼(兩性離子)。各別鹽可藉由熟習此項技術者已知之習用方法獲得,例如藉由使此等在溶劑或分散劑中與有機或無機酸或鹼接觸,或藉由與其他鹽陰離子交換或陽離子交換。If the compounds of the invention contain both acidic and alkaline groups in the molecule, the invention also includes internal salts or betaines (amphoteric ions) in addition to the salt forms mentioned. The respective salts can be obtained by customary methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in a solvent or dispersion, or by anion exchange or cation exchange with other salts.
本發明亦包括本發明之化合物的所有鹽,該等鹽由於較低生理相容性而並不直接適用於藥劑,但可用作例如中間物以用於化學反應或用於製備醫藥學上可接受之鹽。適用於與根本化合物反應以形成醫藥學上可接受之鹽(分別為酸加成或鹼加成鹽)的酸及鹼為熟習此項技術者所已知。類似地,自基本化合物(上文所揭示)製備醫藥學上可接受之鹽之方法為熟習此項技術者所已知且揭示於例如Berge等人Journal of Pharmaceutical Science, 1977年1月第66卷, 第1期及其他來源中。The present invention also includes all salts of the compounds of the present invention which are not directly suitable for use in pharmaceuticals due to low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases suitable for reacting with the base compound to form pharmaceutically acceptable salts (acid addition or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the base compound (disclosed above) are known to those skilled in the art and are disclosed, for example, in Berge et al. Journal of Pharmaceutical Science, Vol. 66, No. 1, January 1977, and other sources.
此外,本文所揭示之化合物可經歷互變異構。在可發生化合物或其前藥之互變異構,例如酮烯醇互變異構之情況下,如例如酮基及烯醇形式之個別形式以及其以任何比率的混合物各自在本發明之範疇內。相同情況適用於立體異構體,如例如對映異構體、順式/反式異構體、非對映異構體、構象異構體及類似者。In addition, the compounds disclosed herein may undergo tautomerism. Where tautomerism of a compound or a prodrug thereof may occur, such as keto-enol tautomerism, each of the individual forms, such as, for example, the keto and enol forms, as well as mixtures thereof in any ratio, are within the scope of the present invention. The same applies to stereoisomers, such as, for example, enantiomers, cis/trans isomers, diastereomers, conformational isomers, and the like.
術語「保護基」係指化合物中可遮掩或改變官能基之特性或整個化合物之特性的部分。用於保護/去保護之化學保護基及策略為此項技術中所熟知。參見例如Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., 紐約, 1991。保護基通常用以遮掩某些官能基之反應性,以輔助所需化學反應之功效,例如從而以有序及計劃方式形成及破壞化學鍵。術語「去保護」係指去除保護基。The term "protecting group" refers to a moiety in a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See, e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to aid the efficiency of a desired chemical reaction, e.g., to form and break chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.
熟習此項技術者應瞭解,當替代性取代基之清單包括其成員(由於其價數需求或其他原因,該等成員不能用於取代特定基團)時,清單意欲由熟習此項技術者之知識理解以僅包括適用於取代特定基團之清單之彼等成員。Those skilled in the art will appreciate that when a list of alternative substituents includes members thereof that cannot be substituted for a particular group due to their valence requirements or other reasons, the list is intended to be understood by those skilled in the art to include only those members of the list that are suitable for substitution for the particular group.
此外,本發明之化合物可以溶劑合物之形式存在,諸如包括為溶劑水或醫藥學上可接受之溶劑合物(諸如醇,特定言之,乙醇)之彼等。「溶劑合物」係藉由溶劑與化合物之相互作用形成。In addition, the compounds of the present invention may exist in the form of a solvent complex, such as those comprising water or a pharmaceutically acceptable solvent complex (such as alcohol, in particular, ethanol). A "solvent complex" is formed by the interaction of a solvent and a compound.
在某些實施例中,提供本文中所描述之化合物或其醫藥學上可接受之鹽或混合物的光學異構體、外消旋體或其其他混合物。視需要,可以藉由此項技術中熟知之方法,例如藉由液相層析來分離異構體。在彼等情形中,單一對映異構體或非對映異構體(亦即,光學活性形式)可以藉由不對稱合成或藉由解析來獲得。解析可例如藉由習知方法實現,諸如在存在解析劑情況下之結晶,或使用例如對掌性高壓液相層析(HPLC)管柱之層析。In certain embodiments, optical isomers, racemates, or other mixtures thereof of the compounds described herein or pharmaceutically acceptable salts or mixtures thereof are provided. If desired, isomers can be separated by methods well known in the art, such as by liquid chromatography. In such cases, single enantiomers or diastereomers (i.e., optically active forms) can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved, for example, by known methods, such as crystallization in the presence of an analytical agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column.
「立體異構體」係指由藉由相同鍵鍵結之相同原子構成但具有不可互換之不同三維結構的化合物。本發明涵蓋各種立體異構體及其混合物且包括「對映異構體」,該對映異構體係指其分子互為不可重疊鏡像的兩種立體異構體。「非對映異構體」為具有至少兩個不對稱原子,但彼此不為鏡像之立體異構體。"Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
在一些實施例中,本文所揭示之化合物及其醫藥學上可接受之鹽可包括不對稱中心,且可因此產生對映異構體、非對映異構體,及就絕對立體化學而言可定義為胺基酸之(R)-或(S)-或(D)-或(L)-之其他立體異構形式。實施例因此包括所有此類可能的異構體,以及其外消旋及光學純形式。具光學活性之(+)及(-)、(R)-及(S)-或(D)-及(L)-異構體可使用對掌性合成子或對掌性試劑來製備,或使用習知技術(例如層析及分步結晶)來解析。用於製備/分離個別對映異構體之習知技術包括自適合的光學純前體進行對掌性合成或使用例如對掌性高壓液相層析(HPLC)對外消旋體(或鹽或衍生物之外消旋體)進行解析。當本文所描述之化合物含有烯系雙鍵或其他幾何不對稱中心時且除非另外說明,否則意欲化合物包括E 及Z 幾何異構體。In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts may include asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms of amino acids that can be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)-. The embodiments therefore include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using known techniques such as chromatography and fractional crystallization. Known techniques for preparing/isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.
包括本文中所描述之化合物或其醫藥學上可接受之鹽、異構體或混合物的本文中所提供之組合物可包括外消旋混合物或含有對映異構體過量之一種對映異構體或單一非對映異構體或非對映異構體混合物的混合物。此等化合物之所有此類異構形式明確地包括在本文中,如同特定地及單獨地列舉每一種異構形式一樣。The compositions provided herein including the compounds described herein or pharmaceutically acceptable salts thereof, isomers or mixtures thereof may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein, as if each isomeric form were specifically and individually listed.
本文中所給出之任何式或結構亦意欲表示化合物的未經標記之形式以及經同位素標記之形式。經同位素標記之化合物具有由本文中給定之化學式所描繪之結構,其例外之處在於一或多個原子經具有選定原子質量或質量數之原子置換。可併入至本發明化合物中之同位素的實例包括氫、碳、氮、氧、磷、氟及氯之同位素,諸如但不限於2 H (氘, D)、3 H (氚)、11 C、13 C、14 C、15 N、18 F、31 P、32 P、35 S、36 Cl及125 I。經各種同位素標記之本發明化合物係例如其中併入諸如3 H、13 C及14 C之放射性同位素的彼等化合物。此等經同位素標記之化合物可適用於代謝研究;反應動力學研究;偵測或成像技術,諸如正電子發射斷層攝影術(PET)或單光子放射電腦斷層攝影術(SPECT),包括藥物或受質組織分佈分析;或適用於患者之放射性治療。本發明的經同位素標記之化合物及其前藥通常可以藉由進行流程中或下文所描述之實例及製備中所揭示之程序,藉由用可容易獲得的經同位素標記之試劑取代非同位素標記之試劑來製備。Any formula or structure given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the chemical formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I. Various isotopically labeled compounds of the present invention are, for example, those into which radioactive isotopes such as 3 H, 13 C, and 14 C are incorporated. These isotopically labeled compounds may be useful in metabolic studies; reaction kinetic studies; detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including analysis of drug or substrate tissue distribution; or for radiotherapy of patients. Isotopically labeled compounds and prodrugs thereof of the present invention may generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.
本發明亦包括本文所揭示之化合物之「氘化類似物」,其中連接至碳原子之1至n個氫經氘置換,其中n為分子中氫之數目。此類化合物呈現增加之代謝抗性,且因此適用於在向哺乳動物(例如人類)投與時增加任何式I化合物之半衰期。參見例如Foster, 「Deuterium Isotope Effects in Studies of Drug Metabolism」, Trends Pharmacol. Sci. 5(12):524-527 (1984)。此類化合物係藉由此項技術中熟知之手段合成,例如藉由採用其中一或多個氫已由氘置換之起始物質。The present invention also includes "deuterated analogs" of the compounds disclosed herein, in which 1 to n hydrogens attached to a carbon atom are replaced with deuterium, wherein n is the number of hydrogens in the molecule. Such compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound of Formula I when administered to mammals (e.g., humans). See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced with deuterium.
本發明之經氘標記或取代之治療性化合物可具有有益的藥物代謝及藥物動力學(drug metabolism and pharmacokinetic;DMPK)特性,該等特性與分佈、代謝及排泄(ADME)相關。用較重同位素(諸如氘)取代可得到由更大代謝穩定性而產生之某些治療性優點,例如增加之活體內半衰期、降低之劑量需求及/或治療指數改良。經18 F標記之化合物可適用於PET或SPECT研究。Deuterium-labeled or substituted therapeutic compounds of the present invention may have beneficial drug metabolism and pharmacokinetic (DMPK) properties, which are related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and/or improved therapeutic index. 18 F-labeled compounds may be suitable for PET or SPECT studies.
可藉由同位素增濃因子來界定此類較重同位素(尤其氘)之濃度。在本發明之化合物中,未明確指定為特定同位素之任何原子意圖表示彼原子之任何穩定同位素。除非另有說明,否則當位置經明確指定為「H」或「氫」時,應理解該位置在其天然豐度同位素組成中具有氫。因此,在本發明之化合物中,任何明確表示為氘(D)之原子意圖表示氘。The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.
此外,本發明提供醫藥組合物,其包含本發明之化合物,或其前藥化合物,或其醫藥學上可接受之鹽或溶劑合物與醫藥學上可接受之載劑一起作為活性成分。In addition, the present invention provides a pharmaceutical composition comprising the compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvent thereof together with a pharmaceutically acceptable carrier as an active ingredient.
「醫藥組合物」意謂一或多種活性成分及構成載劑之一或多種惰性成分,以及由任何兩種或多於兩種成分組合、複合或聚集,或由一或多種成分解離,或由一或多種成分之其他類型之反應或相互作用直接或間接產生的任何產物。因此,本發明之醫藥組合物可以涵蓋藉由將至少一種本發明化合物與醫藥學上可接受之載體摻合而製得的任何組合物。"Pharmaceutical composition" means one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly produced by the combination, complex or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present invention can cover any composition prepared by blending at least one compound of the present invention with a pharmaceutically acceptable carrier.
如本文所使用,「醫藥學上可接受之載劑」包括賦形劑或諸如溶劑、稀釋劑、分散介質、包衣、抗菌劑及抗真菌劑之試劑、等張劑及吸收延遲劑及類似者,該等試劑對本發明化合物或其之使用無害。此類載劑及試劑製備醫藥活性物質之組合物的用途在此項技術中為熟知的(參見例如Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA第17版(1985);及Modern Pharmaceutics, Marcel Dekker, Inc. 第3版(G.S. Banker & C.T. Rhodes編)。As used herein, "pharmaceutically acceptable carriers" include excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents and the like, which are not harmful to the compounds of the present invention or their use. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (G.S. Banker & C.T. Rhodes, eds.).
「IC50 」或「EC50 」係指達至最大所需效果之50%所需的抑制濃度。在本文中之許多情況下,最大所需效果為抑制LPA誘導之LPAR1活化。使用活體外分析(諸如鈣移動分析)獲得此術語,從而評估LPA誘導之LPAR1活性之濃度-依賴性抑制。" IC50 " or " EC50 " refers to the inhibitory concentration required to achieve 50% of the maximal desired effect. In many cases herein, the maximal desired effect is inhibition of LPA-induced LPAR1 activation. This term is obtained using in vitro assays (such as calcium mobilization assays) to assess concentration-dependent inhibition of LPA-induced LPAR1 activity.
「治療」為用於獲得有益或所需結果(包括臨床結果)之途徑。有利或期望臨床結果可包括以下各者中之一或多者:a)抑制該疾病或病況(例如,減少由該疾病或病況產生之一或多種症狀及/或減輕該疾病或病況之程度);b)減緩或停止與該疾病或病況相關之一或多種臨床症狀的發展(例如,使該疾病或病況穩定、預防或延遲該疾病或病況之惡化或進展及/或預防或延遲該疾病或病況之擴散(例如轉移));及/或c)減輕該疾病,亦即使臨床症狀消退(例如,改善疾病病況、提供該疾病或病況之部分或總體緩解、增強另一藥物療法之作用、延遲該疾病之進展、提高生命品質及/或延長存活期)。在一些實施例中,術語「治療(treatment/treating)」意謂出於以下目的投與式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)之化合物或醫藥學上可接受之鹽:(i)延遲疾病之發作,亦即使疾病之臨床症狀不發展或延遲其發展;(ii)抑制疾病,亦即停止臨床症狀之發展;及/或(iii)減輕疾病,亦即使臨床症狀或其嚴重程度消退。"Treatment" is an approach used to obtain beneficial or desired results (including clinical results). Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and/or reducing the severity of the disease or condition); b) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the onset of the disease or condition); and/or c) alleviate the disease, i.e., resolve clinical symptoms (e.g., improve disease symptoms, provide partial or total relief from the disease or condition, enhance the effect of another drug therapy, delay the progression of the disease, improve quality of life, and/or prolong survival). In some embodiments, the term "treatment" or "treating" means administering a compound or a pharmaceutically acceptable salt of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) for the purpose of: (i) delaying the onset of a disease, i.e., preventing or delaying the development of clinical symptoms of a disease; (ii) inhibiting a disease, i.e., stopping the development of clinical symptoms; and/or (iii) alleviating a disease, i.e., causing a regression of clinical symptoms or their severity.
「預防(prevention或preventing)」意謂疾病或病況之促使該疾病或病況之臨床症狀不發展的任何治療。在一些實施例中,化合物可向具有該疾病或病況之風險或具有該疾病或病況之家族史之個體(包括人類)投與。"Prevention" or "preventing" means any treatment of a disease or condition that prevents the clinical symptoms of the disease or condition from developing. In some embodiments, the compound can be administered to an individual (including a human) who is at risk for the disease or condition or has a family history of the disease or condition.
「個體」係指已成為或將成為治療、觀察或實驗之對象的動物,諸如哺乳動物(包括人類)。本文所描述之方法可適用於人類療法及/或獸醫學應用。在一些實施例中,個體為哺乳動物。在一些實施例中,受試者為人類。"Subject" refers to an animal that has been or will be the subject of treatment, observation, or experiment, such as a mammal (including a human). The methods described herein can be applied to human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
本文中所描述之化合物或其醫藥學上可接受之鹽、互變異構體、立體異構體、立體異構體混合物、前藥或氘化類似物的術語「治療有效量」或「有效量」意謂當向個體投與時足以實現治療以提供治療效益(諸如改善症狀或減緩疾病進展)的量。舉例而言,治療有效量可為足以減少響應於LPAR1拮抗劑之疾病或病況之症狀的量。治療有效量可視待治療之個體及疾病或病況、個體之體重及年齡、該疾病或病況之嚴重程度及投與方式而改變,其可以容易地由一者或一般技術者判定。 縮寫及首字母縮寫詞清單
如本文所使用,「LPAR1拮抗劑」係指能夠結合且抑制LPAR1之任何試劑。LPAR1 (亦稱為LPA1 )為結合脂質傳訊分子溶血磷脂酸(LPA)之GPCR。LPAR1之例示性參考序列包括NCBI參考序列NP_001392 (人類蛋白質)、NP_001277415 (小鼠蛋白質)、NM_001401 (人類mRNA)及NM_001290486 (小鼠mRNA)。LPAR1拮抗劑可以用作全部或部分LPAR1促效劑之競爭性抑制劑,或用作反向促效劑。LPAR拮抗劑之活性可藉由此項技術中已知之方法來量測,諸如Castelino等人, 2010 Arthritis Rheum. 2011年5月;63(5): 1405-1415或Swaney等人, J Pharmacol Exp Ther. 2011年3月;336(3):693-700中所描述及引用之彼等方法。As used herein, "LPAR1 antagonist" refers to any agent that is capable of binding to and inhibiting LPAR1. LPAR1 (also known as LPA 1 ) is a GPCR that binds the lipid signaling molecule lysophosphatidic acid (LPA). Exemplary reference sequences for LPAR1 include NCBI reference sequences NP_001392 (human protein), NP_001277415 (mouse protein), NM_001401 (human mRNA), and NM_001290486 (mouse mRNA). LPAR1 antagonists can be used as competitive inhibitors of all or part of LPAR1 agonists, or as inverse agonists. The activity of LPAR antagonists can be measured by methods known in the art, such as those described and cited in Castelino et al., 2010 Arthritis Rheum. 2011 May;63(5):1405-1415 or Swaney et al., J Pharmacol Exp Ther. 2011 Mar;336(3):693-700.
如本文所使用,「ACC抑制劑」係指能夠結合且抑制乙醯基-CoA羧化酶(ACC)之任何試劑。ACC抑制劑可以用作ACC之抑制劑或部分抑制劑。試劑可以為化合物或生物分子(例如,蛋白質或抗體)。ACC抑制劑之活性可以藉由此項技術中已知之方法來量測,諸如美國專利第8,969,557號及/或美國專利第10,208,063號中所描述及引用之彼等方法,該等專利均以全文引用之方式併入本文中。As used herein, "ACC inhibitor" refers to any reagent that is capable of binding to and inhibiting acetyl-CoA carboxylase (ACC). ACC inhibitors can be used as inhibitors or partial inhibitors of ACC. The reagent can be a compound or a biomolecule (e.g., a protein or an antibody). The activity of an ACC inhibitor can be measured by methods known in the art, such as those described and cited in U.S. Patent No. 8,969,557 and/or U.S. Patent No. 10,208,063, which are incorporated herein by reference in their entirety.
如本文所提及,「ASK1抑制劑」可以為能夠使凋亡信號調節激酶1 (ASK1)蛋白質失活之任何試劑。試劑可以為化合物或生物分子(例如,蛋白質或抗體)。ASK1蛋白質活性可以藉由若干不同方法來量測。舉例而言,ASK1蛋白質之活性可以基於ASK1蛋白質磷酸化受質蛋白質之能力來測定。用於鑑別ASK1抑制劑之方法為已知的(參見例如U.S.2007/0276050)。例示性ASK1受質蛋白質包括MAPKK3、MAPKK4、MAPKK6、MAPKK7或其片段。ASK1蛋白質活性亦可以藉由ASK1蛋白質之磷酸化位準來量測,例如蘇胺酸殘基在對應於人類全長ASK1蛋白質之蘇胺酸838 (T838)或小鼠全長ASK1蛋白質之蘇胺酸845 (T845)的ASK1蛋白質中之磷酸化量。舉例而言,在ASK1蛋白質包含全長人類ASK1蛋白質序列之情況下,ASK1抑制劑可減弱全長人類ASK1蛋白質序列中之T838的磷酸化。針對人類ASK1 T838或小鼠ASK1 T845之位點特異性抗體可用以偵測磷酸化位準。As referred to herein, an "ASK1 inhibitor" can be any reagent that is capable of inactivating the apoptosis signal-regulating kinase 1 (ASK1) protein. The reagent can be a compound or a biomolecule (e.g., a protein or an antibody). The activity of the ASK1 protein can be measured by several different methods. For example, the activity of the ASK1 protein can be determined based on the ability of the ASK1 protein to phosphorylate a substrate protein. Methods for identifying ASK1 inhibitors are known (see, e.g., U.S. 2007/0276050). Exemplary ASK1 substrate proteins include MAPKK3, MAPKK4, MAPKK6, MAPKK7, or fragments thereof. ASK1 protein activity can also be measured by the phosphorylation level of the ASK1 protein, such as the phosphorylation amount of the threonine residue in the ASK1 protein corresponding to threonine 838 (T838) of the human full-length ASK1 protein or threonine 845 (T845) of the mouse full-length ASK1 protein. For example, in the case where the ASK1 protein comprises the full-length human ASK1 protein sequence, the ASK1 inhibitor can attenuate the phosphorylation of T838 in the full-length human ASK1 protein sequence. Site-specific antibodies against human ASK1 T838 or mouse ASK1 T845 can be used to detect the phosphorylation level.
如本文所使用,「FXR促效劑」係指能夠結合且激活可以稱為膽酸受體(BAR)或NR1H4 (核受體子族1,族群H,成員4)受體之類法尼醇(farnesoid) X受體(FXR)的任何試劑。FXR促效劑可以用作FXR之促效劑或部分促效劑。試劑可以為化合物或生物分子(例如,蛋白質或抗體)。FXR促效劑之活性可以藉由若干不同方法來量測,例如在活體外分析中使用螢光共振能量轉移(FRET)無細胞分析,如Pellicciari等人, Journal of Medicinal Chemistry, 2002第15卷, 第45:3569-72號中所描述。 化合物 As used herein, "FXR agonist" refers to any agent that is capable of binding to and activating a farnesoid X receptor (FXR), which may be referred to as a bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4) receptor. An FXR agonist may be used as an agonist or partial agonist of FXR. An agent may be a compound or a biomolecule (e.g., a protein or an antibody). The activity of an FXR agonist may be measured by several different methods, such as in an in vitro assay using a fluorescence resonance energy transfer (FRET) cell-free assay, as described in Pellicciari et al., Journal of Medicinal Chemistry, 2002 Vol. 15, No. 45:3569-72. Compounds
在一個實施例中,本文提供一種式(I)化合物, 或其醫藥學上可接受之鹽, 其中: R1 為氫;C1-6 烷基;C2-6 烯基;C2-6 炔基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至10員雜芳基,其中各烷基、烯基、炔基、環烷基、雜環、芳基或雜芳基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫、C1-6 烷基或C3-6 環烷基, 其中各R1A 烷基、環烷基、雜環基、芳基及雜芳基視情況經1至4個相同或不同的R1C 取代,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基,且 其中各R1B1 、R1B2 及R1B3 烷基及各R1B1 、R1B2 及R1B3 環烷基視情況經1至3個鹵素取代,或 R1 為-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各C1-6 烷基或C3-6 環烷基視情況經1至4個相同或不同的R1E 取代,其中各R1E 獨立地選自鹵素;氰基;羥基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-O-R1F1 ;-N(R1F1 )(R1F2 );-C(O)N(R1F1 )(R1F2 );-NR1F1 C(O)R1F2 ;-S(O)0-2 R1F1 ;-S(O)2 N(R1F1 )(R1F2 )及-NR1F1 S(O)2 R1F2 ,其中各R1F1 及R1F2 獨立地為氫或C1-6 烷基,其中各R1E 烷基、環烷基、芳基及雜芳基視情況經1至3個相同或不同的R1G 取代,且其中各R1G 獨立地為C1-4 烷基、C1-4 烷氧基、羥基、鹵素或氰基; R2 為氫或視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C3-10 環烷基之相同或不同取代基取代的C1-6 烷基;或 R2 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C1-6 烷基之相同或不同取代基取代的C3-6 環烷基; 各R3 獨立地選自氘、鹵素、C1-6 烷基、C3-6 環烷基、-O-R2A1 及-N(R2A1 )(R2A2 ),其中該C1-6 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中各R2A1 及R2A2 獨立地為氫或視情況經1至3個相同或不同鹵素取代的C1-3 烷基; n為0、1、2、3或4; R4 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基、-C(O)N(R4A1 )及-N(R4A1 )(R4A2 )之相同或不同取代基取代的C1-6 烷基,其中各R4A1 及R4A2 獨立地為氫、C1-6 烷基或C3-10 環烷基;或 R4 為C3-6 環烷基或具有1或2個獨立地選自氮、氧及硫之雜原子的3至6員雜環基,其中該環烷基或雜環基視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基及C1-4 烷氧基之相同或不同取代基取代; X1 、X2 、X3 及X4 中之每一者獨立地選自CH及N; 各Y1 及Y2 獨立地為氫、氘,或視情況經1至3個獨立地選自氘、鹵素、氰基、C2-3 炔基、C1-4 烷氧基及-C(O)NH-(C1-4 H3-9 )之相同或不同取代基取代的C1-6 烷基;及 Z為C1-8 烷基;C1-6 烷氧基;C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該烷基、烷氧基、環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基、C1-4 烷氧基及C3-6 環烷基之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個選自C1-4 烷氧基及鹵素之相同或不同取代基取代;或 Y1 及Z連同其所連接之碳形成C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自氰基、C1-4 烷基、C1-4 烷氧基、C6-10 芳基及鹵素之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中該C6-10 芳基視情況經1至3個獨立地選自C1-4 烷基、C1-4 烷氧基及鹵素之相同或不同取代基取代,且Y2 為氫或氘。In one embodiment, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl; or a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen; cyano; nitro; pendoxy; C 1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 R 1B2 and R 1B3 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each R 1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 , R 1B2 and R 1B3 alkyl and each R 1B1 , R 1B2 and R 1B3 cycloalkyl are optionally substituted with 1 to 3 halogens, or R 1 is -OR 1D1 or -N(R 1D1 )(R 1D2 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted by 1 to 4 identical or different R 1E , wherein each R 1E is independently selected from halogen; cyano; hydroxyl; pendoxy; C 1-4 alkyl; C 3-10 cycloalkyl; 3 to 10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6 to 10 membered aryl; 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR 1F1 ; -N(R 1F1 )(R 1F2 ); -C(O)N(R 1F1 )(R 1F2 ); -NR 1F1 C(O)R 1F2 ; -S(O) 0-2 R 1F1 ; -S(O) 2 N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O) 2 R 1F2 , wherein each R 1F1 and R 1F2 are independently hydrogen or C 1-6 alkyl, wherein each R 1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R 1G , and wherein each R 1G is independently C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, halogen or cyano; R 2 is hydrogen or C 1-4 alkoxy substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 3-10 cycloalkyl; or R 2 is C 3-6 cycloalkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 1-6 alkyl; each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl , -OR 2A1 and -N(R 2A1 )(R 2A2 ), wherein the C 1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 are independently hydrogen or C 1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R R 4 is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ), wherein each R 4A1 and R 4A2 are independently hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl; or R 4 is C 3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy; X 1 , X 2 , X 3 and X each of Y1 and Y2 is independently selected from CH and N; each of Y1 and Y2 is independently hydrogen, deuterium, or C1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from deuterium , halogen, cyano, C2-3 alkynyl, C1-4 alkoxy and -C(O)NH-( C1-4H3-9 ); and Z is C1-8 alkyl; C1-6 alkoxy; C3-6 cycloalkyl; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl , alkoxy, cycloalkyl, aryl, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy and C 3-6 cycloalkyl, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 identical or different substituents selected from C 1-4 alkoxy and halogen; or Y 1 and Z together with the carbon to which they are attached form a C 3-6 cycloalkyl group; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from cyano, C 1-4 alkyl, C 1-4 alkoxy, C 6-10 aryl and halogen, wherein the C 1-4 alkyl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy and halogen, and Y 2 is hydrogen or deuterium.
在式I化合物或者其醫藥學上可接受之鹽的一些實施例中 R1 為氫;C1-6 烷基;C2-6 烯基;C2-6 炔基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至10員雜芳基,其中各烷基、烯基、炔基、環烷基、雜環、芳基或雜芳基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫或C1-6 烷基, 其中各R1A 烷基、環烷基、雜環基、芳基及雜芳基視情況經1至4個相同或不同的R1C 取代,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基;或 R1 為-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各C1-6 烷基或C3-6 環烷基視情況經1至4個相同或不同的R1E 取代,其中各R1E 獨立地選自鹵素;氰基;羥基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-O-R1F1 ;-N(R1F1 )(R1F2 );-C(O)N(R1F1 )(R1F2 );-NR1F1 C(O)R1F2 ;-S(O)0-2 R1F1 ;-S(O)2 N(R1F1 )(R1F2 )及-NR1F1 S(O)2 R1F2 ,其中各R1F1 及R1F2 獨立地為氫或C1-6 烷基,其中各R1E 烷基、環烷基、芳基及雜芳基視情況經1至3個相同或不同的R1G 取代,且其中各R1G 獨立地為C1-4 烷基、C1-4 烷氧基、羥基、鹵素或氰基; R2 為氫或視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C3-10 環烷基之相同或不同取代基取代的C1-6 烷基;或 R2 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基及C1-6 烷基之相同或不同取代基取代的C3-6 環烷基; 各R3 獨立地選自氘、鹵素、C1-6 烷基、C3-6 環烷基、-O-R2A1 及-N(R2A1 )(R2A2 ),其中該C1-6 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中各R2A1 及R2A2 獨立地為氫或視情況經1至3個相同或不同鹵素取代的C1-3 烷基; n為0、1、2、3或4; R4 為視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷氧基、-C(O)N(R4A1 )及-N(R4A1 )(R4A2 )之相同或不同取代基取代的C1-6 烷基,其中各R4A1 及R4A2 獨立地為氫、C1-6 烷基或C3-10 環烷基;或 R4 為C3-6 環烷基或具有1或2個獨立地選自氮、氧及硫之雜原子的3至6員雜環基,其中該環烷基或雜環基視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基及C1-4 烷氧基之相同或不同取代基取代; X1 、X2 、X3 及X4 中之每一者獨立地選自CH及N; 各Y1 及Y2 獨立地為氫、氘,或視情況經1至3個獨立地選自氘、鹵素、氰基、C2-3 炔基、C1-4 烷氧基及-C(O)NH-(C1-4 H3-9 )之相同或不同取代基取代的C1-6 烷基;及 Z為C1-8 烷基;C1-6 烷氧基;C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該烷基、烷氧基、環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自鹵素、氰基、C1-4 烷基、C1-4 烷氧基及C3-6 環烷基之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個選自C1-4 烷氧基及鹵素之相同或不同取代基取代;或 Y1 及Z連同其所連接之碳形成C3-6 環烷基;C6-12 芳基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至12員雜環基;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至12員雜芳基,其中該環烷基、芳基、雜環基或雜芳基各自視情況經1至3個獨立地選自氰基、C1-4 烷基、C1-4 烷氧基、C6-10 芳基及鹵素之相同或不同取代基取代,其中該C1-4 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中該C6-10 芳基視情況經1至3個獨立地選自C1-4 烷基、C1-4 烷氧基及鹵素之相同或不同取代基取代,且Y2 為氫或氘。In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 is hydrogen; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-10 cycloalkyl; 3 to 10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6 to 10 membered aryl; or 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen; cyano; pendoxy; C 1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl, wherein each R 1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl; or R 1 is -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each C 1-6 alkyl or C 3-6 The 3-6 cycloalkyl group is optionally substituted by 1 to 4 identical or different R 1E groups , wherein each R 1E group is independently selected from halogen; cyano; hydroxyl; pendoxy; C 1-4 alkyl; C 3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR 1F1 ; -N(R 1F1 )(R 1F2 ); -C(O)N(R 1F1 )(R 1F2 ); -NR 1F1 C(O)R 1F2 ; -S(O) 0-2 R 1F1 ; -S(O) 2 N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O) 2 R 1F2 , wherein each R 1F1 and R 1F2 are independently hydrogen or C 1-6 alkyl, wherein each R 1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R 1G , and wherein each R 1G is independently C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, halogen or cyano; R 2 is hydrogen or C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 3-10 cycloalkyl; or R 2 is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy and C 1-6 alkyl; each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), wherein the C 1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C 1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R 4 is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ) wherein each of R 4A1 and R 4A2 is independently hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl; or R 4 is C 3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy; each of X 1 , X 2 , X 3 and X 4 is independently selected from CH and N; each of Y 1 and Y 2 is independently hydrogen, deuterium, or optionally substituted with 1 to 3 identical or different substituents independently selected from deuterium, halogen, cyano, C 2-3 alkynyl, C 1-4 alkoxy; the alkyl radical being selected from the group consisting of -C(O)NH-(C 1-4 H 3-9 ) and -C 1-6 alkyl radical being substituted with the same or different substituents selected from -C(O)NH-(C 1-4 H 3-9 ); and Z is a C 1-8 alkyl radical ; a C 1-6 alkoxy radical; a C 3-6 cycloalkyl radical; a C 6-12 aryl radical; a 3- to 12-membered heterocyclic radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl radical, alkoxy radical, cycloalkyl radical, aryl radical, heterocyclic radical or heteroaryl radical is each optionally substituted with the same or different substituents selected independently from halogen, cyano, C 1-4 alkyl radical, C 1-4 alkoxy radical and C 3-6 cycloalkyl radical, wherein the C 1-4 alkyl radical is optionally substituted with 1 to 3 heteroatoms selected from C 6-12 or Y1 and Z together with the carbon to which they are attached form a C3-6 cycloalkyl group; a C6-12 aryl group; a 3-12 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-12 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 same or different substituents independently selected from cyano, C1-4 alkyl, C1-4 alkoxy, C6-10 aryl and halogen, wherein the C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from C1-4 alkoxy and halogen, and wherein the C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from C1-4 alkoxy and halogen, and wherein the C The 6-10 aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy and halogen, and Y 2 is hydrogen or deuterium.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為式(Ia)化合物: 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia): or a pharmaceutically acceptable salt thereof.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,R2 為氫。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, R 2 is hydrogen.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,R4 為視情況經1至3個獨立地選自氰基及F之相同或不同取代基取代的C1-3 烷基。在式(I)或(Ia)之化合物或其醫藥學上可接受之鹽的一些實施例中,R4 為-CH3 。In some embodiments of the compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, R 4 is C 1-3 alkyl optionally substituted with 1 to 3 identical or different substituents independently selected from cyano and F. In some embodiments of the compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, R 4 is -CH 3 .
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為CH,X2 為CH,X3 為CH,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is CH, X 2 is CH, X 3 is CH, and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為C(R3 ),X2 為CH,X3 為CH,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is C(R 3 ), X 2 is CH, X 3 is CH, and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為C(R3 ),X2 為CH,X3 為C(R3 ),且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X1 is C( R3 ), X2 is CH, X3 is C( R3 ), and X4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為N,X2 為CH,X3 為CH,且X4 為C(R3 )。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is N, X 2 is CH, X 3 is CH, and X 4 is C(R 3 ).
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為CH,X2 為N,X3 為CH,且X4 為C(R3 )。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is CH, X 2 is N, X 3 is CH, and X 4 is C(R 3 ).
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為C(R3 ),X2 為N,X3 為CH,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is C(R 3 ), X 2 is N, X 3 is CH, and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為C(R3 ),X2 為N,X3 為CH,且X4 為C(R3 )。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X1 is C( R3 ), X2 is N, X3 is CH, and X4 is C( R3 ).
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為C(R3 ),X2 為CH,X3 為C(R3 ),且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X1 is C( R3 ), X2 is CH, X3 is C( R3 ), and X4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為N,X2 為CH,X3 為N,且X4 為C(R3 )。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is N, X 2 is CH, X 3 is N, and X 4 is C(R 3 ).
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為C(R3 ),X2 為N,X3 為N,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is C(R 3 ), X 2 is N, X 3 is N, and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為CH,X2 為N,X3 為N,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is CH, X 2 is N, X 3 is N, and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為N,X2 為CH,X3 為CH,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is N, X 2 is CH, X 3 is CH, and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為N,X2 為CH,X3 為N,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X1 is N, X2 is CH, X3 is N, and X4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為CH,X2 為N,X3 為C(R3 ),且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is CH, X 2 is N, X 3 is C(R 3 ), and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,X1 為CH,X2 為N,X3 為CH,且X4 為CH。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X 1 is CH, X 2 is N, X 3 is CH, and X 4 is CH.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,Y2 為氫。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, Y 2 is hydrogen.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIa)化合物: 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIa): or a pharmaceutically acceptable salt thereof.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIb)化合物:。 或其醫藥學上可接受之鹽,其中各R3 可相同或不同。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIb): or a pharmaceutically acceptable salt thereof, wherein each R 3 may be the same or different.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIc)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIc): . or its pharmaceutically acceptable salts.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IId)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IId): . or its pharmaceutically acceptable salts.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIe)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIe): . or its pharmaceutically acceptable salts.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIf)化合物:。 或其醫藥學上可接受之鹽,其中各R3 可相同或不同。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIf): or a pharmaceutically acceptable salt thereof, wherein each R 3 may be the same or different.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIg)化合物:。 或其醫藥學上可接受之鹽,其中各R3 可相同或不同。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIg): or a pharmaceutically acceptable salt thereof, wherein each R 3 may be the same or different.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIh)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIh): . or its pharmaceutically acceptable salts.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIi)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIi): . or a pharmaceutically acceptable salt thereof.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIj)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIj): . or its pharmaceutically acceptable salts.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIk)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIk): . or its pharmaceutically acceptable salts.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIl)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIl): . or its pharmaceutically acceptable salts.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIm)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIm): . or a pharmaceutically acceptable salt thereof.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIn)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIn): . or a pharmaceutically acceptable salt thereof.
在一些實施例中,式(I)或(Ia)化合物或其醫藥學上可接受之鹽為式(IIo)化合物:。 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIo): . or a pharmaceutically acceptable salt thereof.
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為氫。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is hydrogen.
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為C1-6 烷基、C2-6 烯基或C2-6 炔基,各自視情況經1至4個可相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基,且其中各R1B1 、R1B2 及R1B3 烷基及各R1B1 、R1B2 及R1B3 環烷基視情況經1至3個鹵素取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為C1-6 烷基、C2-6 烯基或C2-6 炔基,各自視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫或C1-6 烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),且其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為C1-6 烷基或C2-6 炔基,各自視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素、氰基、羥基、C1-4 烷氧基及C3-6 環烷基。在一些實施例中,R1A 或R1C 中之各鹵素為-F。在一些實施例中,各R1A 獨立地選自-F、-CN、-OH、-OCH3 或環丙基。在一些實施例中,R1A 或R1C 中之各鹵素為-F。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為C1-6 烷基或C2-6 炔基,其各自獨立地經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自-F、-CN、-OH、-OCH3 或環丙基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為-CH3 、-CHF2 、-CF3 、 。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which is optionally substituted with 1 to 4 R1A which may be the same or different, wherein each R1A is independently selected from halogen; cyano; nitro; pendoxy; C1-4 alkyl; C2-6 alkynyl; 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 R 1B2 and R 1B3 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each R 1A is alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with 1 to 4 identical or different R 1C , wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 , R 1B2 and R 1B3 alkyl and each R 1B1 , R 1B2 and R 1B3 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which is optionally substituted with 1 to 4 identical or different R1A , wherein each R1A is independently selected from halogen; cyano; pendoxy; C1-4 alkyl; C2-6 alkynyl; 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl optionally substituted with 1 to 4 identical or different R 1C , wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), and wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) or their pharmaceutically acceptable salts, R 1 is C 1-6 alkyl or C 2-6 alkynyl, each optionally substituted by 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen, cyano, hydroxyl, C 1-4 alkoxy and C 3-6 cycloalkyl. In some embodiments, each halogen in R 1A or R 1C is -F. In some embodiments, each R 1A is independently selected from -F, -CN, -OH, -OCH 3 or cyclopropyl. In some embodiments, each halogen in R 1A or R 1C is -F. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is C1-6 alkyl or C2-6 alkynyl, each of which is independently substituted with 1 to 4 identical or different R1A , wherein each R1A is independently selected from -F, -CN, -OH, -OCH3 or cyclopropyl. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is -CH 3 , -CHF 2 , -CF 3 , .
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各C1-6 烷基或C3-6 環烷基視情況經1至4個相同或不同的R1E 取代,其中各R1E 獨立地選自鹵素;氰基;羥基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-O-R1F1 ;-N(R1F1 )(R1F2 );-C(O)N(R1F1 )(R1F2 );-NR1F1 C(O)R1F2 ;-S(O)0-2 R1F1 ;-S(O)2 N(R1F1 )(R1F2 )及-NR1F1 S(O)2 R1F2 ,其中各R1F1 及R1F2 獨立地為氫或C1-6 烷基,其中各R1E 烷基、環烷基、芳基及雜芳基視情況經1至3個相同或不同的R1G 取代,且其中各R1G 獨立地為C1-4 烷基、C1-4 烷氧基、羥基、鹵素或氰基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各C1-6 烷基或C3-6 環烷基視情況經1至3個相同或不同的-R1E 取代,其中各R1E 獨立地選自鹵素及-C(O)N(R1F1 )(R1F1 ),其中各-R1F1 及-R1F1 獨立地為氫或C1-4 烷基。在一些實施例中,各-R1E 鹵素為-F。在一些實施例中,各-R1G 鹵素為-F。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為-H、-CH3 、-C2 H5 或-C(CH3 )3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1 to 4 identical or different R 1E , wherein each R 1E is independently selected from halogen; cyano; hydroxy; pendant; C 1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR 1F1 ; -N(R 1F1 )(R 1F2 ); -C(O)N(R 1F1 )(R 1F2 ) ; -NR 1F1 C(O)R 1F2 ; -S(O) 0-2 R 1F1 ; -S(O) 2 N(R 1F1 )(R 1F2 ) and -NR 1F1 S(O) 2 R 1F2 , wherein each R 1F1 and R 1F2 are independently hydrogen or C 1-6 alkyl, wherein each R 1E alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 identical or different R 1G , and each R 1G is independently C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, halogen or cyano. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1 to 3 identical or different -R 1E , wherein each R 1E is independently selected from halogen and -C(O)N(R 1F1 )(R 1F1 ), wherein each -R 1F1 and -R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl , wherein each C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1 to 3 identical or different -R 1E , wherein each R 1E is independently selected from halogen and -C(O)N(R 1F1 )(R 1F1 ), wherein each -R 1F1 and -R 1F1 is independently hydrogen or C 1-4 alkyl. In some embodiments, each -R 1E halogen is -F. In some embodiments, each -R 1G halogen is -F. In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof, R 1 is -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently -H, -CH 3 , -C 2 H 5 or -C(CH 3 ) 3 . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is .
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為視情況經1至4個相同或不同的R1A 取代的C3-10 環烷基,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基,且其中各R1B1 及R1B2 烷基以及各R1B1 及R1B2 環烷基視情況經1至3個鹵素取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為視情況經1至4個相同或不同的R1A 取代的C3-10 環烷基,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫或C1-6 烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),且其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為視情況經1至4個相同或不同的R1A 取代的C3-10 環烷基,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至6員雜環基;具有1或2個獨立地選自氮或氧之雜原子的5或6員雜芳基;-OR1B1 ;及-C(O)N(R1B1 )(R1B2 ),其中各R1B1 及R1B2 獨立地為氫、C1-4 烷基或C3-6 環烷基,且其中各R1A C1-4 烷基視情況經1至3個鹵素取代,且R1A 中之各雜芳基視情況經1至3個C1-4 烷基取代,且其中各R1B1 及R1B2 烷基以及各R1B1 及R1B2 環烷基視情況經1至3個鹵素取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為視情況經1至4個相同或不同的R1A 取代的C3-10 環烷基,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至6員雜環基;具有1或2個獨立地選自氮或氧之雜原子的5或6員雜芳基;-OR1B1 ;及-C(O)N(R1B1 )(R1B2 ),其中各R1B1 及R1B2 獨立地為氫或C1-4 烷基,且其中各R1A C1-4 烷基視情況經1至3個鹵素取代,且R1A 中之各雜芳基視情況經1至3個C1-4 烷基取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為環丙基或環丁基,其各自視情況經1至4個各自獨立地選自以下之相同或不同的R1A 取代:-F、-Cl、-CN、=O、-OH、-CH3 、-CH2 F、-CHF2 、-CF3 、-CH2 -OH、-CH2 -NH2 、-OCH3 、-NH2 、-NH-CH2 -CF3 、、-NO2 、環丙基、異㗁唑基、苯基、吡啶基及-C(O)NH2 ,其中各異㗁唑基或吡啶基視情況經1至2個-F或-CH3 取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為環丙基或環丁基,其各自視情況經1至4個各自獨立地選自以下之相同或不同的R1A 取代:-F、-Cl、-CN、=O、-OH、-CH3 、-CH2 F、-CHF2 、-CF3 、-CH2 -OH、-CH2 -NH2 、-OCH3 、-NH2 、環丙基、異㗁唑基、苯基、吡啶基及-C(O)NH2 ,其中各異㗁唑基或吡啶基視情況經1至2個-F或-CH3 取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為環丙基或環丁基,其各自視情況經1至4個各自獨立地選自以下之相同或不同的R1A 取代:-F、-Cl、-CN、=O、-OH、-CH3 、-CH2 F、-CHF2 、-CF3 、-OCH3 、異㗁唑基、吡啶基及-C(O)NH2 ,其中各異㗁唑基或吡啶基視情況經1至2個-CH3 取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在一些實施例中,C3-10 環烷基為C5-10 雙環環烷基。在一些實施例中,C5-10 雙環環烷基為C5-8 橋接雙環環烷基。在一些實施例中,C5-8 橋接雙環環烷基為雙環戊烷基或雙環辛烷基,其各自視情況經1至3個各自獨立地選自以下之相同或不同取代基取代:-F、-Cl、-OH、-CN、-CH3 、-CH2 F、-CHF2 、-CF3 、-O-CH3 、-NH-CO-CH3 、-SO2 -CH3 及氧呾基。在一些實施例中,C5-8 橋接雙環環烷基為雙環戊烷基或雙環辛烷基,其各自視情況經1至3個各自獨立地選自以下之相同或不同取代基取代:-F、-Cl、-OH、-CN、-CH3 、-CH2 F、-CHF2 、-CF3 、-O-CH3 及氧呾基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh),或(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)、(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在一些實施例中,C5-10 雙環環烷基為C5-10 螺雙環環烷基。在一些實施例中,C5-10 螺雙環環烷基為螺戊基、螺己烯基、螺庚基或螺癸基,其各自視情況經1至4個相同或不同的R1A 取代,其中各R1A 各自獨立地選自-F、-Cl、-OH、-CH3 、-CH2 F、-CHF2 、-CF3 、-CN及-O-CH3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a C3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different R1A groups, wherein each R1A group is independently selected from halogen; cyano; nitro; pendooxy; C1-4 alkyl; C3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( R1B1) ; )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 is independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 alkyl and each R 1B1 and R 1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a C3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different R1A groups, wherein each R1A group is independently selected from halogen; cyano; pendooxy; C1-4 alkyl; C3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( R1B1 )(R1 -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O ) N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a C3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different R1A , wherein each R1A is independently selected from halogen; cyano; nitro; pendooxy; C1-4 alkyl; a 3-6 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5 or 6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or oxygen; -OR1B1 ; and -C(O)N( R1B1 )( R1B2 ), wherein each R 1B1 and R 1B2 are independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl, and wherein each R 1A C 1-4 alkyl is optionally substituted with 1 to 3 halogens, and each heteroaryl in R 1A is optionally substituted with 1 to 3 C 1-4 alkyls, and wherein each R 1B1 and R 1B2 alkyl and each R 1B1 and R 1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is a C 3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen; cyano; pendooxy; C 1-4 alkyl; a 3-6 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5 or 6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or oxygen; -OR 1B1 ; and -C(O)N(R 1B1 )(R 1B2 ), wherein each R 1 is C 3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different R 1A, wherein each R 1A is independently selected from halogen; cyano; pendooxy; C 1-4 alkyl; a 3-6 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5 or 6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or oxygen ; R 1B1 and R 1B2 are independently hydrogen or C 1-4 alkyl, and each R 1A C 1-4 alkyl is optionally substituted with 1 to 3 halogens, and each heteroaryl in R 1A is optionally substituted with 1 to 3 C 1-4 alkyls. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 identical or different R 1A each independently selected from the following: -F, -Cl, -CN, =O, -OH, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 -OH, -CH 2 -NH 2 , -OCH 3 , -NH 2 , -NH-CH 2 -CF 3 , , -NO 2 , cyclopropyl, isoxazolyl, phenyl, pyridinyl and -C(O)NH 2 , wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -F or -CH 3 groups. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 identical or different R 1A each independently selected from the following: -F, -Cl, -CN, =O, -OH, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 -OH, -CH 2 -NH 2 , -OCH 3 , -NH 2 , cyclopropyl, isoxazolyl, phenyl, pyridinyl and -C(O)NH 2 , wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -F or -CH 3. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), or pharmaceutically acceptable salts thereof, R 1 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 identical or different R 1A each independently selected from the following: -F, -Cl, -CN, =O, -OH, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCH 3 , isoxazolyl, pyridinyl and -C(O)NH 2 , wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -CH 3 . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is In some embodiments, the C 3-10 cycloalkyl group is a C 5-10 bicyclic cycloalkyl group. In some embodiments, the C 5-10 bicyclic cycloalkyl group is a C 5-8 bridged bicyclic cycloalkyl group. In some embodiments, the C 5-8 bridged bicyclic cycloalkyl group is a bicyclopentyl group or a bicyclooctyl group, each of which is optionally substituted with 1 to 3 identical or different substituents independently selected from the following: -F, -Cl, -OH, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -O-CH 3 , -NH-CO-CH 3 , -SO 2 -CH 3 and oxocarbonyl. In some embodiments, the C 5-8 bridged bicyclic cycloalkyl is dicyclopentyl or dicyclooctyl, each of which is optionally substituted with 1 to 3 identical or different substituents independently selected from the following: -F, -Cl, -OH, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -O-CH 3 and oxocarbonyl. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), (IIo) or their pharmaceutically acceptable salts, R 1 is In some embodiments, the C 5-10 bicyclic cycloalkyl is a C 5-10 spirobicyclic cycloalkyl. In some embodiments, the C 5-10 spirobicyclic cycloalkyl is a spiropentyl, spirohexenyl, spiroheptyl or spirodecanyl, each of which is optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from -F, -Cl, -OH, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CN and -O-CH 3 . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is .
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基,該3至10員雜環基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基,且其中各R1B1 及R1B2 烷基以及各R1B1 及R1B2 環烷基視情況經1至3個鹵素取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基,該3至10員雜環基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫或C1-6 烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為具有1至2個獨立地選自氮、氧及硫之雜原子的3至8員雜環基,該3至8員雜環基視情況經1至4個各自獨立地選自以下之相同或不同的R1A 取代:鹵素、氰基、側氧基或C1-4 烷基,其中各R1A C1-4 烷基視情況經1至3個相同或不同的R1C 取代,且其中各R1C 獨立地為C1-4 烷氧基、鹵素或氰基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為吖呾基、氧呾基、硫雜環丁基、吡咯啶基、二氧戊環基、四氫哌喃基、哌啶基或𠰌啉基,其各自視情況經1至4個各自獨立地選自以下之相同或不同的R1A 取代:-F、-Cl、-OH、-CN、-CH3 、-CH2 F、-CHF2 、-CF3 、-C2 H5 、-CH2 -CF3 及-O-CH3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為吖呾基、氧呾基、硫雜環丁基、吡咯啶基、二氧戊環基、四氫哌喃基或𠰌啉基,其各自視情況經1至4個各自獨立地選自以下之相同或不同的R1A 取代:-F、-Cl、-OH、-CN、-CH3 、-CH2 F、-CHF2 、-CF3 及-O-CH3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 3至10員雜環基形成雙環雜環基。在一些實施例中,雙環雜環基為橋接雙環雜環基。在一些實施例中,橋接雙環雜環基為視情況經1至4個相同或不同的R1A 取代之氧雜雙環己烷基,其中各R1A 獨立地選自-F、-Cl、-OH、-CN、-CH3 、-CH2 F、-CHF2 、-CF3 及-O-CH3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為。在一些實施例中,雙環雜環基為稠合雙環雜環基。在一些實施例中,稠合雙環雜環基為視情況經1至4個相同或不同的R1A 取代之氧雜雙環己烷基,其中各R1A 獨立地選自-F、-Cl、-OH、-CN、-CH3 、-CH2 F、-CHF2 、-CF3 及-O-CH3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為。在一些實施例中,雙環雜環基為螺雙環雜環基。在一些實施例中,螺雙環雜環基為視情況經1至4個相同或不同的取代基取代之氧雜螺庚烷,該(等)取代基各自獨立地選自-F、-Cl、-OH、-CN、-CH3 、-CH2 F、-CHF2 、-CF3 及-O-CH3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 3- to 10-membered heterocyclic group is optionally substituted with 1 to 4 identical or different R, wherein each R is independently selected from halogen; cyano; nitro; pendoxy; C1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 R 1B2 and R 1B3 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclic, aryl and is optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 alkyl and each R 1B1 and R 1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 3- to 10-membered heterocyclic group is optionally substituted with 1 to 4 identical or different R, wherein each R is independently selected from halogen; cyano; pendolo; C1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 3-8 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 3-8 membered heterocyclic group is optionally substituted with 1 to 4 identical or different R 1A each independently selected from halogen, cyano, oxo or C 1-4 alkyl, wherein each R 1A C 1-4 alkyl is optionally substituted with 1 to 3 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkoxy, halogen or cyano. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is azetidinyl, oxazolinyl, thiocyclobutyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl, piperidinyl or oxolinyl, each of which is optionally substituted with 1 to 4 identical or different R selected independently from the following: -F, -Cl, -OH, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -C 2 H 5 , -CH 2 -CF 3 and -O-CH 3 . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is azetyl, oxazoline, thiocyclobutyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl or oxolinyl, each of which is optionally substituted with 1 to 4 identical or different R1A each independently selected from the group consisting of -F, -Cl, -OH, -CN, -CH3 , -CH2F , -CHF2 , -CF3 and -O- CH3 . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R 1 is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 3 to 10 membered heterocyclic group forms a bicyclic heterocyclic group. In some embodiments, the bicyclic heterocyclic group is a bridged bicyclic heterocyclic group. In some embodiments, the bridged bicyclic heterocyclic group is an oxahertzbicyclohexyl group optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from -F, -Cl, -OH, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 and -O-CH 3 . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments, the bicyclic heterocyclic group is a fused bicyclic heterocyclic group. In some embodiments, the fused bicyclic heterocyclic group is an oxahedral hexadecyl group optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from -F, -Cl, -OH, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 and -O-CH 3 . In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is . In some embodiments, the bicyclic heterocyclic group is a spirobicyclic heterocyclic group. In some embodiments, the spirobicyclic heterocyclic group is an oxahedral spiroheptane optionally substituted with 1 to 4 identical or different substituents, each of which is independently selected from -F, -Cl, -OH, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 and -O-CH 3 . In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R 1 is .
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為視情況經1至4個相同或不同的R1A 取代的6至10員芳基,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基,且其中各R1B1 及R1B2 烷基以及各R1B1 及R1B2 環烷基視情況經1至3個鹵素取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為視情況經1至4個相同或不同的R1A 取代的6至10員芳基,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫或C1-6 烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基。在一些實施例中,R1 為視情況經1至4個相同或不同的R1A 取代之苯基,其中各R1A 獨立地選自鹵素、氰基、C1-3 烷基或C1-4 烷氧基。在一些實施例中,R1 為視情況經1至3個相同或不同的R1A 取代之苯基,其中各R1A 獨立地選自-F、Cl、CN或-CH3 。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 6- to 10-membered aryl group optionally substituted with 1 to 4 identical or different R, wherein each R is independently selected from halogen; cyano; nitro; pendooxy; C1-4 alkyl; C3-10 cycloalkyl; a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6- to 10-membered aryl group; a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( R1B1 )(R1 -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O ) N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 is independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 alkyl and each R 1B1 and R 1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 6- to 10-membered aryl group optionally substituted with 1 to 4 identical or different R, wherein each R is independently selected from halogen; cyano; pendoxy; C1-4 alkyl; C3-10 cycloalkyl; a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6- to 10-membered aryl group; a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( R1B1 )( R1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C In some embodiments, R 1 is phenyl optionally substituted with 1 to 4 identical or different R 1A, wherein each R 1A is independently selected from halogen, cyano, C 1-3 alkyl or C 1-4 alkoxy. In some embodiments, R 1 is phenyl optionally substituted with 1 to 3 identical or different R 1A , wherein each R 1A is independently selected from -F, Cl , CN or -CH 3 .
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為具有1至4個獨立地選自氮、氧及硫之雜原子的5至10員雜芳基,該5至10員雜芳基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;硝基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫、C1-6 烷基或C3-6 環烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基,且其中各R1B1 及R1B2 烷基以及各R1B1 及R1B2 環烷基視情況經1至3個鹵素取代。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,R1 為具有1至4個獨立地選自氮、氧及硫之雜原子的5至10員雜芳基,該5至10員雜芳基視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮、氧及硫之雜原子的3至10員雜環基;6至10員芳基;具有1至4個獨立地選自氮、氧或硫之雜原子的5至10員雜芳基;-N(R1B1 )(R1B2 );-O-R1B1 ;-S-R1B1 ;-C(O)N(R1B1 )(R1B2 );-NR1B1 C(O)R1B2 ;-NR1B1 C(O)N(R1B2 )(R1B3 );-S(O)0-2 R1B1 ;-S(O)2 N(R1B1 )(R1B2 )及-NR1B1 S(O)2 R1B2 ,其中各R1B1 、R1B2 及R1B3 獨立地為氫或C1-6 烷基,其中各R1A 烷基、環烷基、雜環基、芳基及視情況經1至4個相同或不同的R1C 取代之雜芳基,且其中各R1C 獨立地為C1-4 烷基、鹵素、氰基、-O-R1D1 或-N(R1D1 )(R1D2 ),其中各R1D1 及R1D2 獨立地為氫或C1-6 烷基。在一些實施例中,R1 為咪唑基、吡唑基、吡啶基、㗁唑基、異㗁唑基、㗁二唑基、吡啶酮基、嘧啶基、嗒𠯤基、苯并異㗁唑基、吡唑并吡啶基、咪唑并吡啶基或苯并咪唑基,其各自視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素;氰基;側氧基;C1-4 烷基;C3-10 環烷基;具有1至4個獨立地選自氮及氧之雜原子的3至10員雜環基;-N(R1B1 )(R1B2 );-O-R1B1 及-S(O)0-2 R1B1 ,其中各R1B1 及R1B2 獨立地為氫或C1-6 烷基,其中各R1A 烷基、環烷基及雜環基視情況經1至4個相同或者不同的R1C 取代,且其中各R1C 獨立地為C1-4 烷基、鹵素或氰基。在一些實施例中,R1 為咪唑基、吡唑基、吡啶基、㗁唑基、異㗁唑基、㗁二唑基、吡啶酮基、嘧啶基、嗒𠯤基、苯并異㗁唑基、吡唑并吡啶基、咪唑并吡啶基或苯并咪唑基,其各自視情況經1至4個相同或不同的R1A 取代,其中各R1A 獨立地選自鹵素、氰基、側氧基、甲基、環丙基、𠰌啉基、-N(R1B1 )(R1B2 )、-O-R1B1 及-S(O)0-2 R1B1 ,其中各R1B1 及R1B2 獨立地為氫或甲基,其中各R1A 甲基、環丙基及𠰌啉基視情況經1至4個相同或不同的R1C 取代,且其中各R1C 獨立地為甲基、鹵素或氰基。在一些實施例中,R1 為咪唑基、吡唑基、吡啶基、㗁唑基、異㗁唑基、㗁二唑基、吡啶酮基、嘧啶基、嗒𠯤基、苯并異㗁唑基、吡唑并吡啶基、咪唑并吡啶基或苯并咪唑基,其各自視情況經1至4個各自獨立地選自以下之相同或不同取代基取代:鹵素、氰基、C1-4 烷基或C1-4 烷氧基。在一些實施例中,R1 為咪唑基、吡唑基或吡啶基,其各自視情況經1至4個各自獨立地選自以下之相同或不同取代基取代:鹵素、氰基、C1-4 烷基或C1-4 烷氧基。在一些實施例中,R1 為咪唑基、吡唑基、吡啶基、㗁唑基、異㗁唑基、㗁二唑基、吡啶酮基、嘧啶基、嗒𠯤基、苯并異㗁唑基、吡唑并吡啶基、咪唑并吡啶基或苯并咪唑基,其各自視情況經1至3個各自獨立地選自-F、-Cl、-CN、-CH3 、-CHF2 、-CF3 、-OCH3 、-NH2 、-N(CH3 )2 、-SO2 -CH3 、 之相同或不同取代基取代。在一些實施例中,R1 為咪唑基、吡唑基或吡啶基,其各自視情況經1至3個各自獨立地選自以下之相同或不同取代基取代:-F、-Cl、-CN或-CH3 。在一些實施例中,R1 為 。在一些實施例中,R1 為 。 在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)或(IIn)化合物或其醫藥學上可接受之鹽的一些實施例中,各R3 獨立地選自氘、鹵素、C1-6 烷基、C3-6 環烷基、-O-R2A1 及-N(R2A1 )(R2A2 ),其中該C1-6 烷基視情況經1至3個獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代,且其中各R2A1 及R2A2 獨立地為氫或視情況經1至3個相同或不同的鹵素取代的C1-4 烷基。在一些實施例中,各R3 獨立地選自視情況經1至3個相同或不同的取代基取代之C1-6 烷基,該(等)取代基獨立地選自鹵素、氰基、C1-4 烷氧基及C3-10 環烷基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)或(IIn)化合物或其醫藥學上可接受之鹽的一些實施例中,R3 為-CH3 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)或(IIn)化合物或其醫藥學上可接受之鹽的一些實施例中,R3 為鹵素。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)或(IIn)化合物或其醫藥學上可接受之鹽的一些實施例中,R3 為-F。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)或(IIn)化合物或其醫藥學上可接受之鹽的一些實施例中,n為0、1或2。在一些實施例中,n為0。在一些實施例中,n為1。在一些實施例中,n為2。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the 5-10 membered heteroaryl group is optionally substituted with 1 to 4 identical or different R, wherein each R is independently selected from halogen; cyano; nitro; pendant; C 1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 R 1B2 and R 1B3 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each R 1A is alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl, and wherein each R 1B1 and R 1B2 alkyl and each R 1B1 and R 1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the 5-10 membered heteroaryl group is optionally substituted with 1 to 4 identical or different R, wherein each R is independently selected from halogen; cyano; pendoxy; C1-4 alkyl; C 3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R 1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R 1B2 ); -NR 1B1 C(O)R 1B2 ; -NR 1B1 C(O)N(R 1B2 )(R 1B3 ); -S(O) 0-2 R 1B1 ; -S(O) 2 N(R 1B1 )(R 1B2 ) and -NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 and R 1B3 are independently hydrogen or C 1-6 alkyl, wherein each R 1A is alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl optionally substituted with 1 to 4 identical or different R 1C , and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, -OR 1D1 or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 are independently hydrogen or C 1-6 alkyl. In some embodiments, R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyrimidinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each of which is optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen; cyano; oxo; C 1-4 alkyl; C 3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen and oxygen; -N(R 1B1 )(R 1B2 ); -OR 1B1 and -S(O) 0-2 R 1B1 , wherein each R 1B1 and R 1B2 are independently hydrogen or C 3-10 cycloalkyl; wherein each R 1A alkyl, cycloalkyl and heterocyclic group is optionally substituted by 1 to 4 identical or different R 1C groups , and wherein each R 1C is independently C 1-4 alkyl, halogen or cyano. In some embodiments, R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyrimidinyl, benzoisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each of which is optionally substituted with 1 to 4 identical or different R 1A , wherein each R 1A is independently selected from halogen, cyano, oxo, methyl, cyclopropyl, oxolinyl, -N(R 1B1 )(R 1B2 ), -OR 1B1 and -S(O) 0-2R 1B1 , wherein each R 1B1 and R 1B2 are independently hydrogen or methyl, wherein each R 1A methyl, cyclopropyl and oxolinyl are optionally substituted with 1 to 4 identical or different R 1A In some embodiments, R 1 is substituted with 1 to 4 identical or different substituents independently selected from the following: halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R 1 is substituted with 1 to 4 identical or different substituents independently selected from the following: halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R 1 is substituted with 1 to 4 identical or different substituents independently selected from the following: halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyrimidinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each of which is optionally substituted with 1 to 3 independently selected from -F, -Cl, -CN, -CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -NH 2 , -N(CH 3 ) 2 , -SO 2 , -CH 3 , ... In some embodiments, R 1 is imidazolyl, pyrazolyl or pyridyl, each of which is optionally substituted with 1 to 3 identical or different substituents independently selected from the following: -F, -Cl, -CN or -CH 3 . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi) or (IIn), or a pharmaceutically acceptable salt thereof, each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR 2A1 and -N(R 2A1 )(R 2A2 ), wherein the C 1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C 1-4 alkyl substituted with 1 to 3 identical or different halogens. In some embodiments, each R 3 is independently selected from C 1-6 alkyl, optionally substituted with 1 to 3 identical or different substituents, said substituent(s) being independently selected from halogen, cyano, C 1-4 alkoxy and C 3-10 cycloalkyl. In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi) or (IIn) or a pharmaceutically acceptable salt thereof, R 3 is -CH 3. In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi) or (IIn) or a pharmaceutically acceptable salt thereof, R 3 is halogen. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, R is -F . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
在式(I)或(Ia)化合物或其醫藥學上可接受之鹽的一些實施例中,各Y1 及Y2 獨立地為氫、氘或視情況經1至3個獨立地選自鹵素、氰基、C2-3 炔基、C1-4 烷氧基及-C(O)NH-(C1-4 H3-9 )之相同或不同取代基取代的C1-6 烷基。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,Y1 為氫、氘或視情況經1至3個獨立地選自鹵素、氰基、C2-3 炔基、C1-4 烷氧基及-C(O)NH-(C1-4 H3-9 )之相同或不同取代基取代的C1-6 烷基。在一些實施例中,Y1 為視情況經1至3個各自獨立地選自鹵素、氰基及C1-4 烷氧基之相同或不同取代基取代的C1-4 烷基,且Y2 為氫。在一些實施例中,Y1 為視情況經1至3個各自獨立地選自-F、-Cl、-CN及-O-CH3 之相同或不同取代基取代的甲基。在一些實施例中,Y1 為-CH3 或-CH2 F。In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, each of Y1 and Y2 is independently hydrogen, deuterium or C1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C2-3 alkynyl, C1-4 alkoxy and -C(O)NH-( C1-4H3-9 ). In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, Y is hydrogen, deuterium or C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C 2-3 alkynyl, C 1-4 alkoxy and -C(O)NH-(C 1-4 H 3-9 ). In some embodiments, Y is C 1-4 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano and C 1-4 alkoxy, and Y is hydrogen. In some embodiments, Y 1 is methyl optionally substituted with 1 to 3 identical or different substituents each independently selected from -F, -Cl, -CN, and -O-CH 3. In some embodiments, Y 1 is -CH 3 or -CH 2 F.
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,Z為視情況經1至3個各自獨立地選自鹵素、氰基、C1-4 烷基、C1-4 烷氧基及C3-6 環烷基之相同或不同取代基取代的C6-12 芳基,其中該C1-4 烷基視情況經1至3個各自獨立地選自C1-4 烷氧基及鹵素之相同或不同取代基取代。在一些實施例中,Z為視情況經1至3個各自獨立地選自鹵素及C1-4 烷基之相同或不同取代基取代的苯基。在一些實施例中,Z為視情況經1至3個各自獨立地選自-F及-Cl之相同或不同取代基取代的苯基。在一些實施例中,Z為 。在一些實施例中,Z為具有1-3個獨立地選自氮、氧及硫之雜原子的5或6員雜芳基,其中該雜芳基視情況經1至3個各自獨立地選自鹵素及C1-4 烷基之相同或不同取代基取代。在一些實施例中,Z為視情況經1至3個各自獨立地選自-F、-Cl、-Br及-CH3 之相同或不同取代基取代的吡啶基。在一些實施例中,Z為 。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, Z is C6-12 aryl optionally substituted with 1 to 3 identical or different substituents each independently selected from halogen, cyano, C1-4 alkyl, C1-4 alkoxy and C3-6 cycloalkyl, wherein the C1-4 alkyl is optionally substituted with 1 to 3 identical or different substituents each independently selected from C1-4 alkoxy and halogen. In some embodiments, Z is phenyl optionally substituted with 1 to 3 identical or different substituents each independently selected from halogen and C1-4 alkyl. In some embodiments, Z is phenyl optionally substituted with 1 to 3 identical or different substituents each independently selected from -F and -Cl. In some embodiments, Z is In some embodiments, Z is a 5- or 6-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen and C 1-4 alkyl. In some embodiments, Z is a pyridyl group optionally substituted with 1 to 3 identical or different substituents independently selected from -F, -Cl, -Br and -CH 3. In some embodiments, Z is .
在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,Y1 為-CH3 且Z為 。在式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的一些實施例中,Y1 為-CH3 且Z為。In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, Y 1 is -CH 3 and Z is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, Y 1 is -CH 3 and Z is .
在一些實施例中,式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽係選自由以下組成之群: , 或其醫藥學上可接受之鹽。In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: , or their pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)、(IIo)化合物或其醫藥學上可接受之鹽係選自由以下組成之群: ,或其醫藥學上可接受之鹽。In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), (IIo) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or their pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIo)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIe)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIe) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIe)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I), (Ia) or (IIe) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.
在一些實施例中,式(I)、(Ia)或(IIe)化合物或其醫藥學上可接受之鹽為:, 或其醫藥學上可接受之鹽。 醫藥組合物及投與模式 In some embodiments, the compound of formula (I), (Ia) or (IIe) or a pharmaceutically acceptable salt thereof is: , or a pharmaceutically acceptable salt thereof. Pharmaceutical composition and administration mode
此外,本發明提供醫藥組合物,其包含本發明之至少一種化合物,或其前藥化合物,或其醫藥學上可接受之鹽或溶劑合物與醫藥學上可接受之載劑一起作為活性成分。In addition, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvent thereof, together with a pharmaceutically acceptable carrier as an active ingredient.
本發明之醫藥組合物可另外包含一或多種其他化合物作為活性成分,如前藥化合物或其他酶抑制劑。The pharmaceutical compositions of the present invention may further comprise one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.
組合物適合於經口、經直腸、局部、非經腸(包括皮下、肌內及靜脈內)、眼(經眼)、經肺(經鼻或頰內吸入)或經鼻投與,儘管在任何給定情況之大多數合適途徑將視所治療之病況之性質及嚴重程度及活性成分之性質而定。其可方便地以單位劑型呈現且藉由藥劑學技術中熟知之任何方法來製備。The composition is suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (transoral), pulmonary (nasal or intrabuccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition to be treated and the nature of the active ingredient. It may be conveniently presented in unit dosage form and prepared by any method well known in the art of pharmacy.
在實際使用中,本發明之化合物可以作為緊密摻合物中之活性成分與醫藥載劑根據習知醫藥混合技術組合。載劑可視投與(例如經口或非經腸(包括靜脈內))所需之製劑形式而採取多種形式。在製備用於口服劑型之組合物時,在諸如(例如)懸浮液、酏劑及溶液之口服液體製劑;或諸如澱粉、糖、微晶纖維素、稀釋劑、成粒劑、潤滑劑、黏合劑、崩解劑及類似者之載劑的情況下,在諸如(例如)粉劑、硬質及軟質膠囊及錠劑之口服固體製劑的情況下(其中相較於液體製劑,固體口服製劑為較佳的),可採用常用醫藥介質中之任一者,諸如(例如)水、二醇、油、醇、調味劑、防腐劑、著色劑及類似者。In practical use, the compounds of the present invention can be combined as active ingredients in intimate admixtures with pharmaceutical carriers according to conventional pharmaceutical mixing techniques. The carrier can take a variety of forms depending on the form of preparation required for administration (e.g., oral or parenteral (including intravenous)). In preparing compositions for oral dosage forms, in the case of oral liquid preparations such as suspensions, elixirs and solutions; or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like, in the case of oral solid preparations such as powders, hard and soft capsules and tablets (where solid oral preparations are preferred over liquid preparations), any of the usual pharmaceutical media such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be employed.
因為錠劑及膠囊易於投與,所以其代表最有利之口服單位劑型,在此情況下使用固體醫藥載劑。必要時,錠劑可藉由標準水性或非水性技術來包覆。此類組合物及製劑應含有至少0.1%之活性化合物。此等組合物中之活性化合物之百分比當然可變化且可宜在單位重量之約2%至約60%之間。此類治療上適用之組合物中之活性化合物的量使得將獲得有效劑量。活性化合物亦可以例如液滴或噴霧形式經鼻內投與。Tablets and capsules represent the most advantageous oral unit dosage forms because they are easy to administer, in which case solid pharmaceutical carriers are used. Tablets may be coated by standard aqueous or non-aqueous techniques, if necessary. Such compositions and formulations should contain at least 0.1% of the active compound. The percentage of the active compound in such compositions may of course vary and may preferably be between about 2% and about 60% of the unit weight. The amount of the active compound in such therapeutically applicable compositions is such that an effective dose will be obtained. The active compound may also be administered intranasally, for example, in the form of drops or sprays.
錠劑、丸劑、膠囊及其類似物亦可含有諸如黃蓍膠、阿拉伯膠、玉米澱粉或明膠之黏合劑;諸如磷酸二鈣之賦形劑;諸如玉米澱粉、馬鈴薯澱粉、褐藻酸之崩解劑;諸如硬脂酸鎂之潤滑劑;及諸如蔗糖、乳糖或糖精之甜味劑。當單位劑型為膠囊時,除以上類型之材料以外,該單位劑型可含有液體載劑,諸如脂肪油。Tablets, pills, capsules and the like may also contain binders such as gum tragacanth, gum arabic, corn starch or gelatin; formulators such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, in addition to the above types of materials, the unit dosage form may contain a liquid carrier such as a fatty oil.
各種其他材料可以包衣形式存在或用以改變劑量單位之物理形式。舉例而言,錠劑可經包覆有蟲膠、糖或兩者。除活性成分之外,糖漿或酏劑可含有作為甜味劑之蔗糖、作為防腐劑之對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、染料及調味劑(諸如櫻桃香料或橙香料)。Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with insect glue, sugar, or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetener, methyl and propyl parabens as preservatives, dyes, and flavorings such as cherry or orange flavor.
在一些實施例中,本發明之化合物亦可用作具有各種反陽離子之鹽以得到經口有效的調配物。In some embodiments, the compounds of the present invention may also be used as salts with various anti-cations to obtain orally effective formulations.
本發明之化合物亦可非經腸投與。此等活性化合物之溶液或懸浮液可在與諸如羥基-丙基纖維素之界面活性劑適當混合之水中製備。亦可以在甘油、液態聚乙二醇及其於油中之混合物中製備分散液。在普通的儲存及使用條件下,此等製劑含有防腐劑,用以防止微生物生長。The compounds of the present invention may also be administered parenterally. Solutions or suspensions of the active compounds may be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
適合於可注射用途之醫藥形式包括無菌水溶液或分散液及用於臨時製備無菌可注射溶液或分散液之無菌粉劑。在所有情況下,形式必須為無菌的,且必須在易於注射性存在之程度上為流體。其在製造及儲存條件下必須穩定,且必須保藏以防諸如細菌及真菌之微生物之污染作用。載劑可以為溶劑或分散介質,其含有例如水、乙醇、多元醇(例如丙三醇、丙二醇及液體聚乙二醇)、其適合混合物及植物油。Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it is easy to inject. It must be stable under the conditions of manufacture and storage and must be preserved to prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.
可採用用於為尤其人類之哺乳動物提供有效劑量的本發明之化合物的任何適合之投與途徑。舉例而言,可採用經口、經直腸、局部、非經腸、眼部、經肺、經鼻及其類似途徑。劑型包括錠劑、糖衣錠、分散液、懸浮液、溶液、膠囊、乳膏、軟膏、氣溶膠及其類似劑型。在一些實施例中,本發明之化合物經口投與。 套組 Any suitable route of administration for providing an effective dose of the compounds of the present invention to mammals, especially humans, may be used. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal and the like may be used. Dosage forms include tablets, dragees, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. In some embodiments, the compounds of the present invention are administered orally. Kits
本文亦提供套組,其包括本發明之化合物或其醫藥學上可接受之鹽、互變異構體、立體異構體、立體異構體混合物、前驅藥或氘化類似物,及適合的封裝。在一個實施例中,套組進一步包括使用說明書。在一個態樣中,套組包括本發明之化合物或其醫藥學上可接受之鹽、互變異構體、立體異構體、立體異構體混合物、前藥或氘化類似物,及使用化合物治療適應症,包括本文所描述之疾病或病況的標籤及/或說明書。Also provided herein are kits comprising a compound of the invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomer mixture, prodrug or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomer mixture, prodrug or deuterated analog thereof, and a label and/or instructions for using the compound to treat an indication, including a disease or condition described herein.
本文亦提供製品,其包括處於適合的容器中之本文中所描述之化合物或其醫藥學上可接受之鹽、互變異構體、立體異構體、立體異構體混合物、前藥或氘化類似物。容器可為小瓶、廣口瓶、安瓿、預裝載注射器及靜脈袋。 治療方法及用途 Also provided herein are articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomer mixture, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, pre-filled syringe, and intravenous bag. Treatment methods and uses
本發明進一步係關於本文所揭示之化合物用於經由藉由該等化合物結合LPAR1來治療及/或預防疾病及/或病況的用途。此外,本發明係關於該等化合物用於製備用以經由藉由該等化合物結合LPAR1來治療及/或預防疾病及/或病況之藥劑的用途。The present invention further relates to the use of the compounds disclosed herein for treating and/or preventing diseases and/or conditions by binding to LPAR1 by the compounds. In addition, the present invention relates to the use of the compounds for preparing a medicament for treating and/or preventing diseases and/or conditions by binding to LPAR1 by the compounds.
如本文中所提及之藥劑可藉由習知製程來製備,包括根據本發明之化合物與醫藥學上可接受之載劑的組合。The pharmaceutical compositions mentioned herein can be prepared by known processes, comprising combining a compound according to the present invention with a pharmaceutically acceptable carrier.
在一些實施例中,本文提供一種治療及/或預防有需要的患者之LPAR1介導之疾病或病況的方法,其包含向患者投與治療有效量之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽,或包含式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物的組合物或其醫藥學上可接受之鹽。In some embodiments, provided herein is a method for treating and/or preventing an LPAR1-mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof.
在一些實施例中,LPAR1介導之疾病或病況包括其中存在及/或觀察到絕對或相對過量之LPA的彼等疾病或病況。In some embodiments, LPAR1-mediated diseases or conditions include those diseases or conditions in which an absolute or relative excess of LPA is present and/or observed.
在一些實施例中,LPAR1介導之疾病或病況包括纖維化、創傷癒合、癌症、疼痛、呼吸道病症、過敏性病症、神經系統病症、心臟血管病症或炎性病症。In some embodiments, the LPAR1-mediated disease or condition comprises fibrosis, wound healing, cancer, pain, respiratory disorders, allergic disorders, nervous system disorders, cardiovascular disorders, or inflammatory disorders.
在一些實施例中,LPAR1介導之疾病或病況為間質性肺病(ILD)。在一些實施例中,間質性肺病(ILD)為非特異性間質性肺炎(NSIP)、類肉瘤病、石棉沉著病、與職業性暴露相關之ILD、進行性纖維化ILD、特發性間質性肺炎(IIP)、結締組織疾病相關之間質性肺病(CTD-ILD)、類風濕性關節炎相關之ILD、硬皮病相關之ILD或外因性肺泡炎。In some embodiments, the disease or condition of LPAR1 mediation is interstitial lung disease (ILD). In some embodiments, interstitial lung disease (ILD) is non-specific interstitial pneumonia (NSIP), sarcoidosis, asbestosis, ILD associated with occupational exposure, progressive fibrosing ILD, idiopathic interstitial pneumonia (IIP), interstitial lung disease associated with connective tissue disease (CTD-ILD), ILD associated with rheumatoid arthritis, ILD associated with scleroderma, or extrinsic alveolitis.
在一些實施例中,LPAR1介導之疾病或病況為慢性腎病(CKD)。在一些實施例中,慢性腎病為補體腎小球病變、膜性腎小球病變、多囊性腎病、IgA腎病、局灶節段性腎小球硬化症(FSGS)或奧爾波特症候群(Alport Syndrome)。In some embodiments, the LPAR1-mediated disease or condition is chronic kidney disease (CKD). In some embodiments, the chronic kidney disease is glomerulopathy, membranous glomerulopathy, polycystic nephropathy, IgA nephropathy, focal segmental glomerulosclerosis (FSGS) or Alport Syndrome.
在一些實施例中,LPAR1介導之疾病或病況包括纖維化。在一些實施例中,纖維化包括肺纖維化、腎纖維化、肝纖維化、眼纖維化或心臟纖維化。In some embodiments, the LPAR1-mediated disease or condition comprises fibrosis. In some embodiments, fibrosis comprises pulmonary fibrosis, renal fibrosis, hepatic fibrosis, ocular fibrosis or cardiac fibrosis.
在一些實施例中,LPAR1介導之疾病或病況包括肺纖維化。在一些實施例中,肺纖維化包括特發性肺纖維化(IPF)。在一些實施例中,肺纖維化包括進行性纖維變性間質性肺病(PF-ILD)。在一些實施例中,肺纖維化包括繼發於全身性炎性疾病之肺纖維化,該全身性炎性疾病諸如類風濕性關節炎、硬皮病、狼瘡、隱原性纖維化肺泡炎、輻射誘導之纖維化、慢性阻塞性肺病(COPD)、硬皮病、慢性哮喘、矽肺病、石棉誘導之肺或胸膜纖維化、急性肺損傷及急性呼吸窘迫(包括細菌肺炎誘導的、外傷誘導的、病毒性肺炎誘導的、呼吸器誘導的、非肺敗血症誘導的及吸入誘導的)。In some embodiments, the LPAR1-mediated disease or condition comprises pulmonary fibrosis. In some embodiments, pulmonary fibrosis comprises idiopathic pulmonary fibrosis (IPF). In some embodiments, pulmonary fibrosis comprises progressive fibrotic interstitial lung disease (PF-ILD). In some embodiments, pulmonary fibrosis includes pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-septicemia-induced, and inhalation-induced).
在一些實施例中,LPAR1介導之疾病或病況包括腎纖維化。在一些實施例中,腎纖維化包括與以下相關之慢性腎病變:損傷/纖維化(腎纖維化),例如,繼發於全身性炎性疾病之腎小球性腎炎,該全身性炎性疾病諸如狼瘡及硬皮病、糖尿病、腎小球腎炎、局灶節段性腎小球硬化症、IgA腎病、高血壓、同種異體移植及奧爾波特;腸纖維化,例如,硬皮病及輻射誘導之腸纖維化。In some embodiments, LPAR1-mediated diseases or conditions include renal fibrosis. In some embodiments, renal fibrosis includes chronic renal pathologies associated with: injury/fibrosis (renal fibrosis), for example, glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allogeneic transplantation, and Allport; intestinal fibrosis, for example, scleroderma and radiation-induced intestinal fibrosis.
在一些實施例中,LPAR1介導之疾病或病況包括肝纖維化。在一些實施例中,肝纖維化包括肝硬化、酒精誘導之肝纖維化、非酒精性脂肪變性肝炎(NASH)、膽管損傷、原發性膽汁性肝硬化、感染或病毒誘導之肝纖維化(例如,慢性HCV感染)及自體免疫肝炎。In some embodiments, LPAR1-mediated diseases or conditions include liver fibrosis. In some embodiments, liver fibrosis includes cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection) and autoimmune hepatitis.
在一些實施例中,LPAR1介導之疾病或病況包括頭頸部纖維化,例如輻射誘導的。In some embodiments, the LPAR1-mediated disease or condition comprises head and neck fibrosis, such as radiation-induced.
在一些實施例中,LPAR1介導之疾病或病況包括角膜疤痕形成,例如,由於雷射輔助之原位角膜重塑術(laser-assisted in situ keratomileusis;LASIK)、角膜移植或小梁切除術(trabeculectomy)。在一些實施例中,式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽用於改良由角膜手術,諸如LASIK或白內障角手術引起之角膜靈敏度下降、由角膜變性引起之角膜靈敏度下降,及由此引起之乾眼症狀。在一些實施例中,式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽用於治療或預防眼發炎及過敏性結膜炎、春季角膜結膜炎及乳頭狀結膜炎。在一些實施例中,式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽用於治療或預防休格倫病(Sjogren disease)或具有乾眼症狀的發炎疾病。In some embodiments, the LPAR1-mediated disease or condition comprises corneal scarring, for example, due to laser-assisted in situ keratomileusis (LASIK), corneal transplantation or trabeculectomy. In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof is used to improve decreased corneal sensitivity caused by corneal surgery, such as LASIK or cataract surgery, decreased corneal sensitivity caused by corneal degeneration, and dry eye symptoms caused thereby. In some embodiments, the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) or their pharmaceutically acceptable salts are used to treat or prevent ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis. In some embodiments, the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) or their pharmaceutically acceptable salts are used to treat or prevent Sjogren's disease or inflammatory diseases with dry eye symptoms.
在一些實施例中,LPAR1介導之疾病或病況包括另一種纖維變性病況,諸如肥厚性疤痕及瘢痕瘤(例如,燒傷誘導或手術)、類肉瘤病、硬皮病、脊髓損傷/纖維化、骨髓纖維化、血管再狹窄、動脈粥樣硬化、動脈硬化、韋格納氏肉芽腫病(Wegener's granulomatosis)、混合性結締組織病及佩洛尼氏病(Peyronie's disease)。In some embodiments, the LPAR1-mediated disease or condition comprises another fibrotic condition, such as hypertrophic scars and keloids (e.g., burn-induced or surgical), sarcoidosis, scleroderma, spinal cord injury/fibrosis, bone marrow fibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.
在一些實施例中,LPAR1介導之疾病或病況包括疼痛。在一些實施例中,疼痛包括神經痛。在一些實施例中,疼痛包括急性疼痛。在一些實施例中,疼痛包括慢性疼痛。In some embodiments, the LPAR1-mediated disease or condition comprises pain. In some embodiments, the pain comprises neuropathic pain. In some embodiments, the pain comprises acute pain. In some embodiments, the pain comprises chronic pain.
在一些實施例中,LPAR1介導之疾病或病況包括癌症。在一些實施例中,癌症包括卵巢癌、大腸癌、前列腺癌、乳癌、黑素瘤、頭頸癌、腸癌(大腸直腸癌)及甲狀腺癌。在一些實施例中,癌症包括實體腫瘤,諸如(諸如膀胱、腸、大腦、乳房、子宮內膜、心臟、腎臟、肺、淋巴組織(淋巴瘤)、卵巢、胰臟或其他內分泌器官(甲狀腺)、前列腺、皮膚(黑素瘤或基底細胞癌)之彼等腫瘤或在疾病之任何階段存在或不存在癌轉移之血液腫瘤(諸如白血病)。在一些實施例中,癌症包括急性淋巴母細胞白血病、急性骨髓白血病、腎上腺皮質癌、肛門癌、闌尾癌、星形細胞瘤、非典型畸胎樣/桿狀瘤、基底細胞癌、膽管癌、膀胱癌、骨癌(骨肉瘤及惡性纖維組織細胞瘤)、腦幹神經膠質瘤、腦瘤、大腦及脊髓腫瘤、乳癌、支氣管腫瘤、伯基特淋巴瘤(Burkitt lymphoma)、子宮頸癌、慢性淋巴球性白血病、慢性骨髓性白血病、大腸癌、大腸直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、胚胎腫瘤、子宮內膜癌、室管膜母細胞瘤、室管膜瘤、食道癌、尤文氏肉瘤(ewing sarcoma)腫瘤家族、眼癌、視網膜母細胞瘤、膽囊癌、胃癌、胃腸道類癌瘤、胃腸道基質瘤(GIST)、胃腸道基質細胞瘤、生殖細胞瘤、神經膠質瘤、毛細胞白血病、頭頸癌、肝細胞(肝臟)癌症、霍奇金淋巴瘤(hodgkin lymphoma)、下咽癌、眼內黑色素瘤、胰島細胞瘤(內分泌胰臟)、卡波西肉瘤(Kaposi sarcoma)、腎癌、蘭格漢氏細胞組織細胞增多病(Langerhans cell histiocytosis)、喉癌、白血病、急性淋巴母細胞白血病、急性骨髓白血病、慢性淋巴球性白血病、慢性骨髓性白血病、毛細胞白血病、肝癌、非小細胞肺癌、小細胞肺癌、伯基特淋巴瘤、皮膚T細胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、淋巴瘤、瓦爾登斯特倫巨球蛋白血症(Waldenstrom macroglobulinemia)、神經管胚細胞瘤、髓上皮瘤、黑素瘤、間皮瘤、口腔癌、慢性骨髓性白血病、骨髓白血病、多發性骨髓瘤、鼻咽癌、神經母細胞瘤、非霍奇金淋巴瘤、非小細胞肺癌、口癌、口咽癌、骨肉瘤、骨骼惡性纖維組織細胞瘤、卵巢癌、卵巢上皮癌、卵巢生殖細胞瘤、卵巢低度惡性潛伏腫瘤、胰臟癌、乳頭狀瘤症、副甲狀腺癌、陰莖癌、咽癌、中間分化之松果體實質性腫瘤、松果體母細胞瘤及幕上原始神經外胚層瘤、腦垂體瘤、漿細胞贅瘤/多發性骨髓瘤、胸膜肺母細胞瘤、原發性中樞神經系統淋巴瘤、前列腺癌、直腸癌、腎細胞(腎臟)癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、肉瘤、尤文氏肉瘤腫瘤家族、肉瘤、卡波西肉瘤、塞紮里症候群(Sezary syndrome)、皮膚癌、小細胞肺癌、小腸癌、軟組織肉瘤、鱗狀細胞癌、胃癌、幕上原始神經外胚層瘤、T細胞淋巴瘤、睪丸癌、喉癌、胸腺瘤及胸腺癌、甲狀腺癌、尿道癌、子宮癌、子宮肉瘤、陰道癌、外陰癌、瓦爾登斯特倫巨球蛋白血症、威爾姆斯腫瘤(Wilms tumor)。In some embodiments, the LPAR1-mediated disease or condition comprises cancer. In some embodiments, cancer comprises ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer (colorectal cancer) and thyroid cancer. In some embodiments, cancer comprises solid tumors, such as (such as bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma) or blood tumors (such as leukemia) with or without metastasis at any stage of the disease. In some embodiments, cancer comprises solid tumors, such as (such as bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma) or blood tumors (such as leukemia) with or without metastasis at any stage of the disease. In the embodiments, the cancer includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, coccygeal cancer, astrocytoma, atypical teratoid/bar tumor, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer (osteosarcoma and malignant fibromyoma), brain stem neurofibroma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma lymphoma), cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, colorectal cancer, cranio-pharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, neuroglioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma lymphoma), hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia macroglobulinemia), medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibroblastic tumor of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant latent tumor, pancreatic cancer, papilloma, epithelial cell carcinoma, Thyroid cancer, penile cancer, pharyngeal cancer, intermediately differentiated pineal parenchymal tumor, pinealoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell adenocarcinoma/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family of tumors, sarcoma, Kaposi's sarcoma, Sezary syndrome syndrome), skin cancer, small cell lung cancer, small intestinal cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms tumor.
在一些實施例中,LPAR1介導之疾病或病況包括呼吸道或過敏性病症。在一些實施例中,呼吸道或過敏性病症包括哮喘、細支氣管周纖維化、閉塞性細支氣管炎及慢性阻塞性肺病(COPD)。在一些實施例中,COPD包括慢性支氣管炎或肺氣腫、肺高血壓、肺間質纖維化及/或氣道炎症及囊腫性纖維化。在一些實施例中,呼吸道疾病包括成人呼吸窘迫症候群及過敏性(外因性)哮喘、非過敏性(內因性)哮喘、急性重度哮喘、慢性哮喘、臨床哮喘、夜間哮喘、過敏原誘導之哮喘、阿司匹林(aspirin)敏感性哮喘、運動誘導之哮喘、等二氧化碳過度換氣(isocapnic hyperventilation)、兒童發作型哮喘、成人發作型哮喘、咳嗽變異性哮喘、職業性哮喘、類固醇耐藥性哮喘、季節性哮喘、季節性過敏性鼻炎、常年性過敏性鼻炎及缺氧。In some embodiments, LPAR1-mediated diseases or conditions include respiratory or allergic diseases. In some embodiments, respiratory or allergic diseases include asthma, peribronchial fibrosis, obstructive bronchitis, and chronic obstructive pulmonary disease (COPD). In some embodiments, COPD includes chronic bronchitis or emphysema, pulmonary hypertension, pulmonary interstitial fibrosis and/or airway inflammation and cystic fibrosis. In some embodiments, respiratory diseases include adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, and hypoxia.
在一些實施例中,LPAR1介導之疾病或病況包括神經系統病症。在一些實施例中,神經系統病症包括阿茲海默氏病(Alzheimer's Disease)、腦水腫、腦缺血、中風、多發性硬化症、神經病、帕金森氏病(Parkinson's Disease)、鈍器或手術創傷之後發現的神經病況(包括手術後認知功能障礙及脊髓或腦幹損傷),以及諸如退化性椎間盤疾病及坐骨神經痛之病症之神經學態樣。In some embodiments, LPAR1-mediated diseases or conditions include nervous system disorders. In some embodiments, nervous system disorders include Alzheimer's Disease, brain edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's Disease, neurological conditions found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brain stem damage), and neurological aspects of diseases such as degenerative disc disease and sciatica.
在一些實施例中,LPAR1介導之疾病或病況包括心臟血管病症。在一些實施例中,心臟血管病症包括心律不整(心房或腦室或兩者);動脈粥樣硬化及其後遺症;絞痛;心節律紊亂;心肌缺血;心肌梗塞;心臟或血管動脈瘤;脈管炎;中風;肢體、器官或組織之周邊阻塞性動脈病;腦、心臟或其他器官或組織缺血之後的再灌注損傷;內毒素、手術或創傷性休克;高血壓;心臟瓣膜病;心臟衰竭;血壓異常;休克;血管收縮(包括與偏頭痛相關之血管收縮);血管異常及受限於單個器官或組織之心臟血管功能不全。In some embodiments, the LPAR1-mediated disease or condition comprises a cardiovascular disorder. In some embodiments, the cardiovascular disorder includes arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral obstructive arterial disease of a limb, organ or tissue; reperfusion injury following ischemia of the brain, heart or other organs or tissues; endotoxin, surgical or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities and cardiovascular insufficiency limited to a single organ or tissue.
在一些實施例中,LPAR1介導之疾病或病況包括肺纖維化、腎纖維化、肝纖維化、疤痕形成、哮喘、鼻炎、慢性阻塞性肺病(COPD)、肺高血壓、肺間質纖維化、關節炎、過敏、牛皮癬、炎性腸病、成人呼吸窘迫症候群、心肌梗塞、動脈瘤、中風、癌症、疼痛、增生性病症及炎性病況。In some embodiments, LPAR1-mediated diseases or conditions include pulmonary fibrosis, renal fibrosis, hepatic fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary interstitial fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders, and inflammatory conditions.
在一些實施例中,LPAR1介導之疾病或病況為肝病。在一些實施例中,肝病為C型肝炎、肝癌、家族性混合型高脂質血症、非酒精性脂肪肝病(NAFLD)、進展性家族性肝內膽汁淤積症、原發性膽汁性肝硬化(PBC)或(PSC)。在一些實施例中,肝病為PSC。在一些實施例中,肝病包含門靜脈高血壓。在一些實施例中,肝癌包含肝細胞癌(HCC)、膽管癌、血管肉瘤(angiosarcoma)或血管肉瘤(hemangiosarcoma)。在一些實施例中,肝癌包含HCC。在一些實施例中,NAFLD包含脂肪變性。在一些實施例中,NAFLD包含NASH。在一些實施例中,NAFLD或NASH包含肝纖維化。在一些實施例中,NAFLD或NASH包含肝硬化。在一些實施例中,NAFLD或NASH包含代償性肝硬化。在一些實施例中,NAFLD或NASH包含失代償性肝纖維化。在一些實施例中,NAFLD包含HCC。在一些實施例中,肝病為NASH。In some embodiments, the LPAR1-mediated disease or condition is a liver disease. In some embodiments, the liver disease is hepatitis C, liver cancer, familial mixed hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC) or (PSC). In some embodiments, the liver disease is PSC. In some embodiments, the liver disease comprises portal hypertension. In some embodiments, liver cancer comprises hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma or hemangiosarcoma. In some embodiments, liver cancer comprises HCC. In some embodiments, NAFLD comprises fatty degeneration. In some embodiments, NAFLD comprises NASH. In some embodiments, NAFLD or NASH comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises cirrhosis. In some embodiments, NAFLD or NASH comprises compensatory cirrhosis. In some embodiments, NAFLD or NASH comprises decompensated liver fibrosis. In some embodiments, NAFLD comprises HCC. In some embodiments, the liver disease is NASH.
在一些實施例中,本文提供一種治療及/或預防有需要之患者之NAFLD或NASH的方法,其包含向患者投與治療有效量之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽,或包含式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物的組合物或其醫藥學上可接受之鹽。在一些實施例中,NAFLD或NASH包含肝纖維化。在一些實施例中,NAFLD或NASH包含肝硬化。在一些實施例中,肝硬化為代償性肝硬化。在一些實施例中,肝硬化為失代償性肝硬化。在一些實施例中,NAFLD或NASH包含HCC。In some embodiments, provided herein is a method for treating and/or preventing NAFLD or NASH in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD or NASH comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises cirrhosis. In some embodiments, cirrhosis is compensatory cirrhosis. In some embodiments, cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH comprises HCC.
在一些實施例中,本文提供一種預防有需要之患者之肝臟疾病或病況的方法,包含向患者投與治療有效量之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽,或包含式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物的組合物或其醫藥學上可接受之鹽。在一些實施例中,肝病或病況為肝纖維化。在一些實施例中,肝臟疾病或病況為肝硬化。在一些實施例中,肝硬化為代償性肝硬化。在一些實施例中,肝硬化為失代償性肝硬化。在一些實施例中,肝臟疾病或病況為HCC。In some embodiments, provided herein is a method of preventing a liver disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease or condition is liver fibrosis. In some embodiments, the liver disease or condition is cirrhosis. In some embodiments, the cirrhosis is compensatory cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, the liver disease or condition is HCC.
在一些實施例中,本發明係關於根據式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽的用途,其用於製備用於預防及/或治療本文所揭示之LPAR1介導之疾病或病況的藥物。 劑量 In some embodiments, the present invention relates to the use of a compound according to formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of an LPAR1-mediated disease or condition disclosed herein. Dosage
所採用活性成分之有效劑量可視所採用之特定化合物、投與模式、所治療之病況及所治療之病況之嚴重程度而變化。熟習此項技術者可輕易確定此類劑量。The effective dosage of the active ingredient employed may vary depending on the specific compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by one skilled in the art.
當治療或預防本發明之化合物所針對之LPAR1介導之疾病或病況時,當以約0.1毫克至約300毫克/公斤動物體重之日劑量投與本發明之化合物時,獲得通常令人滿意之結果。在一些實施例中,本發明之化合物以單個每日劑量或以一天兩次至六次之分次劑量或以緩釋形式給與。對於大部分大型哺乳動物,總每日劑量為約1毫克至約1000毫克,或約1毫克至約50毫克。就70 kg成人而言,每日總劑量將通常為約0.1毫克至約200毫克。此給藥方案可經調節以提供最佳治療反應。在一些實施例中,每日總劑量為約1毫克至約900毫克、約1毫克至約800毫克、約1毫克至約700毫克、約1毫克至約600毫克、約1毫克至約400毫克、約1毫克至約300毫克、約1毫克至約200毫克、約1毫克至約100毫克、約1毫克至約50毫克、約1毫克至約20毫克或約1毫克至約10毫克。When treating or preventing LPAR1-mediated diseases or conditions targeted by the compounds of the present invention, generally satisfactory results are obtained when the compounds of the present invention are administered in a daily dose of about 0.1 mg to about 300 mg/kg of animal body weight. In some embodiments, the compounds of the present invention are administered in a single daily dose or in divided doses two to six times a day or in a sustained release form. For most large mammals, the total daily dose is about 1 mg to about 1000 mg, or about 1 mg to about 50 mg. For a 70 kg adult, the total daily dose will generally be about 0.1 mg to about 200 mg. This dosing regimen can be adjusted to provide the best therapeutic response. In some embodiments, the total daily dose is about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 20 mg, or about 1 mg to about 10 mg.
本申請案之化合物或其組合物可使用上文所描述之任何適合模式每天投與一次、兩次、三次或四次。另外,用化合物投與或治療可持續多天;舉例而言,對一個治療週期,治療通常將持續至少7天、14天或28天。治療週期常常與各週期之間約1至28天、通常約7天或約14天之休止期交替。在其他實施例中,治療週期亦可為連續的。The compounds or compositions of the present application may be administered once, twice, three times or four times a day using any suitable mode described above. In addition, administration or treatment with the compound may continue for multiple days; for example, for a treatment cycle, treatment will generally continue for at least 7 days, 14 days or 28 days. Treatment cycles are often alternating with rest periods of about 1 to 28 days, usually about 7 days or about 14 days between each cycle. In other embodiments, treatment cycles may also be continuous.
在一些實施例中,本文所提供之方法包含向個體投與約1至800 mg本文所描述之化合物的初始日劑量,及以增量增加劑量直至達成臨床功效為止。可以使用約5、10、25、50或100 mg之增量來增加劑量。劑量可以每天、每隔一天、每週兩次或每週一次地增加。 組合 In some embodiments, the methods provided herein comprise administering to a subject an initial daily dose of about 1 to 800 mg of a compound described herein, and increasing the dose in increments until clinical efficacy is achieved. The dose may be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week. Combinations
在一些實施例中,本文所提供之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽與一或多種額外治療劑組合投與以治療或預防本文所揭示之疾病或病況。在一些實施例中,一或多種額外治療劑為一種、兩種、三種或四種額外治療劑。在一些實施例中,一或多種額外治療劑為一種額外治療劑。在一些實施例中,一或多種額外治療劑為兩種額外治療劑。在一些實施例中,一或多種額外治療劑為三種額外治療劑。在一些實施例中,一或多種額外治療劑為四種額外治療劑。In some embodiments, a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.
在一些實施例中,本文所提供之醫藥組合物具有本文所提供之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物,或其醫藥學上可接受之鹽及一或多種額外治療劑。在一些實施例中,一或多種額外治療劑為一種、兩種、三種或四種額外治療劑。在一些實施例中,一或多種額外治療劑為一種額外治療劑。在一些實施例中,一或多種額外治療劑為兩種額外治療劑。在一些實施例中,一或多種額外治療劑為三種額外治療劑。在一些實施例中,一或多種額外治療劑為四種額外治療劑。In some embodiments, the pharmaceutical compositions provided herein have a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.
在一些實施例中,一或多種額外治療劑係選自血管收縮素轉化酶(ACE)抑制劑、腺苷A3受體促效劑、脂聯素受體促效劑、AKT蛋白激酶抑制劑、AMP激酶活化劑、AMP活化蛋白激酶(AMPK)活化劑、澱粉素受體促效劑、血管收縮素II AT-1受體拮抗劑、雄激素受體促效劑、細胞凋亡信號調整激酶1 (ASK1)抑制劑、ATP檸檬酸鹽解離酶抑制劑、脂蛋白元C3 (APOC3)拮抗劑、自噬蛋白調節劑、自分泌運動因子抑制劑、Axl酪胺酸激酶受體抑制劑、Bax蛋白刺激劑、生物活性脂質、 降鈣素促效劑、大麻受體調節子、凋亡蛋白酶抑制劑、凋亡蛋白酶-3刺激劑、組織蛋白酶抑制劑(例如,組織蛋白酶B抑制劑)、窖蛋白1抑制劑、CCR2趨化激素拮抗劑、CCR3趨化激素拮抗劑、CCR5趨化激素拮抗劑、CD3拮抗劑、氯通道刺激劑、膽固醇增溶劑、CNR1抑制劑、週期素D1抑制劑、細胞色素P450 7A1抑制劑、細胞色素P450 2E1 (CYP2E1)抑制劑、二醯甘油O醯基轉移酶1抑制劑(DGAT1)抑制劑、二醯甘油O醯基轉移酶1抑制劑(DGAT2)抑制劑、CXCR4趨化激素拮抗劑、二肽基肽酶、IV抑制劑、內皮唾酸蛋白調節劑、內皮氧化氮合成酶刺激劑、伊紅趨素配位體抑制劑、細胞外基質蛋白調節劑、類法尼醇X受體促效劑、脂肪酸合成酶抑制劑、FGF1受體促效劑、纖維母細胞活化蛋白(FAP)抑制劑、纖維母細胞生長因子受體配位體(例如,FGF-15、FGF-19、FGF-21)、魚油、半乳糖凝集素-3抑制劑、升糖素受體促效劑、類升糖素肽1受體促效劑、糖皮質激素受體拮抗劑、葡萄糖6-磷酸1-去氫酶抑制劑、麩醯胺酸酶抑制劑、麩胱甘肽前體、G蛋白偶聯之膽酸受體1促效劑、G蛋白偶聯之受體84拮抗劑、刺蝟(Hh)調節劑、C型肝炎病毒NS3蛋白酶抑制劑、肝細胞核因子4 α調節劑(HNF4A)、肝細胞成長因子調節劑、組蛋白脫乙醯基酶抑制劑、HMG CoA還原酶抑制劑、11β-羥基類固醇去氫酶(11β-HSD1)抑制劑、低氧誘導性因子-2 α抑制劑、IL-1β拮抗劑、IL-6受體促效劑、IL-10促效劑、IL-11拮抗劑、IL-17拮抗劑、回腸鈉膽酸共運輸蛋白抑制劑、 胰島素敏化劑、胰島素配位體促效劑、胰島素受體促效劑、整合素調節劑、整合素拮抗劑白細胞介素-1受體相關之激酶4(IRAK4)抑制劑、Jak2酪胺酸激酶抑制劑、己酮糖激酶(KHK)抑制劑、克囉索β刺激劑、瘦素、瘦素類似物、5-脂肪加氧酶抑制劑、脂蛋白脂肪酶抑制劑、肝X受體、LPL基因刺激劑、溶血磷脂酸-1受體(LPAR-1)拮抗劑、離胺醯氧化酶同系物2 (LOXL2)抑制劑、LXR反向促效劑、巨噬細胞甘露糖受體1調節劑、基質金屬蛋白酶(MMP)抑制劑、MCH受體-1拮抗劑、MEKK-5蛋白激酶抑制劑、膜銅胺氧化酶(VAP-1)抑制劑、甲硫胺酸胺基肽酶-2抑制劑、甲基CpG結合蛋白2調節劑、微小RNA-132 (miR-132)拮抗劑、微小RNA-21 (miR-21)抑制劑、粒線體解偶聯劑、混合譜系激酶-3抑制劑、 髓磷脂鹼性蛋白刺激劑、NACHT PYD域蛋白3 (NLRP3)抑制劑、NAD依賴性脫乙醯基酶長壽蛋白-1刺激劑、NADPH氧化酵素抑制劑(NOX)、菸鹼酸受體1促效劑、P2X7嘌呤受體調節劑、P2Y13嘌呤受體刺激劑、PDE 3抑制劑、PDE 4抑制劑、PDE 5抑制劑、PDGF受體β調節劑、肽基-脯胺醯基順式-反式異構酶A抑制劑、苯丙胺酸羥化酶刺激劑、磷脂酶C抑制劑、PPAR α促效劑、PPAR γ促效劑、PPAR δ促效劑、PPAR γ調節劑、PPAR α/δ促效劑、PPAR α/γ/δ促效劑、蛋白酶活化受體-2拮抗劑、蛋白激酶調節劑、ρ相關蛋白激酶2 (ROCK2)抑制劑、亞硝基麩胱甘肽還原酶(GSNOR)酶抑制劑、鈉葡萄糖轉運體-2 (SGLT2)抑制劑、SREBP轉錄因子抑制劑、 STAT-1抑制劑、STAT-3調節劑、硬脂醯基CoA去飽和酶-1抑制劑、亞硝基麩胱甘肽還原酶(GSNOR)酶抑制劑、細胞介素傳訊抑制因子-1刺激劑、細胞介素傳訊抑制因子-3刺激劑、脾酪胺酸激酶(SYK)抑制劑、轉型生長因子β (TGF-β)、TGF-β拮抗劑(例如,TGF-β1拮抗劑、TGF-β2拮抗劑、TGF-β3拮抗劑、潛伏TGF β錯合物調節劑)、TGF-β受體拮抗劑、轉型生長因子β活化激酶1 (TAK1)、甲狀腺激素受體β促效劑、Toll樣受體(TLR)-4拮抗劑、穀氨醯胺轉胺酶抑制劑、腫瘤壞死因子α (TNFα)配位體抑制劑、腫瘤進行基因座2 (Tpl2)激酶抑制劑、酪胺酸激酶受體調節劑、GPCR調節劑、核激素受體調節劑、WNT調節劑、YAP/TAZ調節劑及連蛋白抑制劑。In some embodiments, one or more additional therapeutic agents are selected from angiotensin converting enzyme (ACE) inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP kinase activators, AMP activated protein kinase (AMPK) activators, starch receptor agonists, angiotensin II AT-1 receptor antagonists, androgen receptor agonists, apoptosis signal regulating kinase 1 (ASK1) inhibitors, ATP citrate lyase inhibitors, apolipoprotein C3 (APOC3) antagonists, autophagy protein regulators, autocrine motor factor inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, Calcium-lowering hormone agonists, cannabinoid receptor modulators, apoptosis inhibitors, apoptosis stimulators-3, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin-1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT1) inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase, IV inhibitors, endosialin regulators, endothelial nitric oxide synthase stimulators, eosin ligand inhibitors, extracellular matrix protein regulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activation protein (FAP) inhibitors, Fibroblast growth factor receptor ligands (e.g., FGF-15, FGF-19, FGF-21), fish oil, galectin-3 inhibitors, glucagon receptor agonists, glucagon-like peptide 1 receptor agonists, glucocorticoid receptor antagonists, glucose 6-phosphate 1-dehydrogenase inhibitors, glutaminase inhibitors, glutathione precursors, G protein-coupled cholic acid receptor 1 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 α regulator (HNF4A), hepatocyte growth factor regulator, histone deacetylase inhibitor, HMG CoA reductase inhibitor, 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitor, hypoxia-inducing factor-2 α inhibitor, IL-1β antagonist, IL-6 receptor agonist, IL-10 agonist, IL-11 antagonist, IL-17 antagonist, ileal sodium bile acid symporter inhibitor, Insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, Jak2 tyrosine kinase inhibitors, ketokinase (KHK) inhibitors, clonidine beta stimulators, leptin, leptin analogs, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptors, LPL gene stimulators, lysophosphatidic acid-1 receptor (LPAR-1) antagonists, aminoacyl oxidase homolog 2 (LOXL2) inhibitor, LXR inverse agonist, macrophage mannose receptor 1 regulator, matrix metalloproteinase (MMP) inhibitor, MCH receptor-1 antagonist, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG binding protein 2 regulator, microRNA-132 (miR-132) antagonist, microRNA-21 (miR-21) inhibitor, mitochondrial uncoupling agent, mixed spectrum kinase-3 inhibitor, myelin alkaline protein stimulator, NACHT PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase longevity protein-1 stimulators, NADPH oxidase inhibitors (NOX), niacin receptor 1 agonists, P2X7 purine receptor modulators, P2Y13 purine receptor stimulators, PDE 3 inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor β modulators, peptidyl-prolinyl cis-trans isomerase A inhibitors, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, PPAR α agonists, PPAR γ agonists, PPAR δ agonists, PPAR γ modulators, PPAR α/δ agonists, PPAR α/γ/δ agonists, protease-activated receptor-2 antagonists, protein kinase regulators, rho-related protein kinase 2 (ROCK2) inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, STAT-3 regulators, stearyl CoA desaturase-1 inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, interleukin signaling inhibitor-1 stimulators, interleukin signaling inhibitor-3 stimulators, spleen tyrosine kinase (SYK) inhibitors, transformation growth factor β (TGF-β), TGF-β antagonists (e.g., TGF-β1 antagonists, TGF-β2 antagonists, TGF-β3 antagonists, latent TGF β complex modulators), TGF-β receptor antagonists, transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonists, Toll-like receptor (TLR)-4 antagonists, glutamine transaminase inhibitors, tumor necrosis factor α (TNFα) ligand inhibitors, tumor progression locus 2 (Tpl2) kinase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, YAP/TAZ modulators and zonulin inhibitors.
一或多種額外治療劑之非限制性實例包括 ACE抑制劑,諸如依那普利(enalapril); 乙醯基CoA羧化酶(ACC)抑制劑,諸如NDI-010976 (菲索科司他(firsocostat))、DRM-01、吉卡賓(gemcabene)、PF-05175157、QLT-091382或PF-05221304; 乙醯基CoA羧化酶/二醯甘油O醯基轉移酶2抑制劑,諸如PF-07055341; 乙醛去氫酶抑制劑,諸如ADX-629; 腺苷受體促效劑,諸如CF-102(那末德松(namodenoson))、CF-101、CF-502或CGS21680; 脂聯素受體促效劑,諸如ADP-355或ADP-399; 澱粉素/降鈣素受體促效劑,諸如KBP-042或KBP-089; AMP活化蛋白激酶刺激劑,諸如PXL-770或O-304; AMP激酶活化劑/ATP檸檬酸鹽裂解酶抑制劑,諸如貝派度酸(bempedoic acid)(ETC-1002、ESP-55016); AMP活化蛋白激酶/內皮氧化氮合成酶/NAD依賴性脫乙醯基酶長壽蛋白-1刺激劑,諸如NS-0200(白胺酸+二甲雙胍+西地那非(sildenafil)); 雄激素受體促效劑,諸如LPCN-1144; 血管收縮素II AT-1受體拮抗劑,諸如依貝沙坦(irbesartan); 血管生成素相關蛋白-3抑制劑,諸如IONIS-ANGPTL3-LRx; 自分泌運動因子抑制劑,諸如PAT-505、PAT-048、GLPG-1690、X-165、PF-8380、AM-063或BBT-877; Axl酪胺酸激酶受體抑制劑,諸如貝西替尼(bemcentinib)(BGB-324, R-428); Bax蛋白質刺激劑,諸如CBL-514; 生物活性脂質,諸如DS-102; 大麻素受體1型(CNR1)抑制劑,諸如納馬珠單抗(namacizumab)、GWP-42004、REV-200或CRB-4001; 凋亡蛋白酶抑制劑,諸如恩利卡生(emricasan); Pan組織蛋白酶B抑制劑,諸如VBY-376; 泛組織蛋白酶抑制劑,諸如VBY-825; CCR2/CCR5趨化激素拮抗劑,諸如森尼韋若(cenicriviroc)、馬拉維若(maraviroc)、CCX-872或WXSH-0213; CCR2趨化激素拮抗劑,諸如丙帕鍺(propagermanium); CCR2趨化激素/血管收縮素II AT-1受體拮抗劑,諸如DMX-200或DMX-250; CCR2/CCR5趨化激素拮抗劑及FXR促效劑,諸如LJC-242 (曲匹氟索(tropifexor)+塞尼維羅克(cenivriviroc)); CCR3趨化激素拮抗劑,諸如柏替木單抗(bertilimumab); 氯離子通道刺激劑,諸如科普斯酮(cobiprostone)或魯比前列酮(lubiprostone); CD3拮抗劑,諸如NI-0401 (弗拉魯單抗(foralumab)); CXCR4趨化激素拮抗劑,諸如AD-214; 二甘油脂醯基轉移酶1 (DGAT1)抑制劑,諸如GSK-3008356; 二醯甘油O醯基轉移酶1 (DGAT1)/細胞色素P450 2E1抑制劑(CYP2E1),諸如SNP-610; 二甘油脂醯基轉移酶2 (DGAT2)抑制劑,諸如IONIS-DGAT2Rx或PF-06865571; 二肽基肽酶IV抑制劑,諸如利格列汀(linagliptin)或依格列汀(evogliptin); 伊紅趨素配位體抑制劑,諸如柏替木單抗或CM-101; 細胞外基質蛋白調節劑,諸如CNX-024; 類法尼醇X受體(FXR)促效劑,諸如AGN-242266、AGN-242256、EP-024297、RDX-023、BWL-200、AKN-083、EDP-305、GNF-5120、GS-9674、LMB-763、奧貝膽酸、Px-102、Px-103、M790、M780、M450、M-480、MET-409、PX20606、EYP-001、TERN-101、TC-100、INT-2228; 類法尼醇X受體(FXR)/G蛋白偶聯之膽酸受體1(TGR5)促效劑,諸如INT-767; 脂肪酸合成酶抑制劑,諸如TVB-2640; FGF受體促效劑/克囉索β刺激劑,諸如BFKB-8488A (RG-7992); 纖維母細胞生長因子19 (rhFGF19)/細胞色素P450 (CYP) 7A1抑制劑,諸如NGM-282; 纖維母細胞生長因子21(FGF-21)配位體,諸如BMS-986171、BIO89-100、B-1344或BMS-986036; 纖維母細胞生長因子21 (FGF-21)/類升糖素肽1 (GLP-1)促效劑,諸如YH-25723 (YH-25724;YH-22241)或AKR-001; 魚油組合物,諸如二十碳五烯酸乙酯(Vascepa® ); 半乳糖凝集素-3抑制劑,諸如GR-MD-02、GB-1107 (Gal-300)或GB1211 (Gal-400); 類升糖素肽1受體(GLP1R)促效劑,諸如AC-3174、利拉魯肽(liraglutide)、輔因子(MEDI-0382)、艾塞那肽(exenatide)、SAR-425899、LY-3305677、HM-15211、YH-25723、YH-GLP1、RPC-8844、PB-718或索馬魯肽(semaglutide); 糖皮質激素受體拮抗劑,諸如CORT-118335 (米瑞科里蘭特(miricorilant)); 葡萄糖6-磷酸1-去氫酶抑制劑,諸如ST001; G蛋白偶聯之膽酸受體1(TGR5)促效劑,諸如RDX-009或INT-777; 熱衝擊蛋白質47 (HSP47)抑制劑,諸如ND-L02-s0201; HMG CoA還原酶抑制劑,諸如阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、匹伐他汀(pitavastatin)、普伐他汀(pravastatin)、羅素他汀(rosuvastatin)或辛伐他汀(simvastatin); 低氧誘導因子-2α抑制劑,諸如PT-2567; IL-10促效劑,諸如peg-伊洛白介素(peg-ilodecakin); 回腸鈉膽酸共運輸蛋白抑制劑,諸如odevixibat (A-4250)、volixibat乙醇鉀水合物(SHP-262)、GSK2330672、CJ-14199或依洛昔巴(A-3309); 胰島素敏化劑,諸如KBP-042、MSDC-0602K、MSDC-5514、Px-102、RG-125 (AZD4076)、VVP-100X、CB-4211或ETI-101; 胰島素配位體/胰島素受體促效劑,諸如ORMD-0801; 整合素拮抗劑,諸如IDL-2965; IL-6受體促效劑,諸如KM-2702; 己酮糖激酶(KHK)抑制劑,諸如PF-06835919; β克囉索(KLB)-FGF1c促效劑,諸如MK-3655 (NGM-313); 5-脂肪加氧酶抑制劑,諸如泰魯斯特(tipelukast) (MN-001)、DS-102 (AF-102); 脂蛋白脂肪酶抑制劑,諸如CAT-2003; LPL基因刺激劑,諸如阿利潑金(alipogene tiparvovec); 肝臟X受體(LXR)調節劑,諸如PX-L603、PX-L493、BMS-852927、T-0901317、GW-3965或SR-9238; 溶血磷脂酸-1受體拮抗劑,諸如BMT-053011、UD-009 (CP-2090)、AR-479、ITMN-10534、BMS-986020或KI-16198; 離胺醯氧化酶同源物2抑制劑,諸如辛圖珠單抗(simtuzumab)或PXS-5382A (PXS-5338); 巨噬細胞甘露糖受體1調節劑,諸如替馬諾噻(tilmanocept)-Cy3 (鎝Tc 99m替馬諾噻); 膜銅胺氧化酶(VAP-1)抑制劑,諸如TERN-201; MEKK-5蛋白激酶(ASK-1)抑制劑,諸如GS-4997、SRT-015或GS-444217、GST-HG-151; MCH受體-1拮抗劑,諸如CSTI-100 (ALB-127158); 甲硫胺酸胺基肽酶-2抑制劑,諸如ZGN-839、ZGN-839或ZN-1345; 甲基CpG結合蛋白質2調節劑,諸如巰乙胺; 粒線體去偶合劑,諸如2,4-二硝基苯酚或HU6; 混合譜系激酶-3抑制劑,諸如URMC-099-C; 髓磷脂鹼性蛋白刺激劑,諸如奧利索西(olesoxime); NADPH氧化酶1/4抑制劑,諸如GKT-831或APX-311; 菸鹼酸受體1促效劑,諸如ARI-3037MO; 硝唑尼特(Nitazoxinide); NACHT LRR PYD域蛋白質3 (NLRP3)抑制劑,諸如KDDF-201406-03、NBC-6、IFM-514或JT-194(JT-349); 核受體調節劑,諸如DUR-928 (DV-928); P2X7嘌呤受體調節劑,諸如SGM-1019; P2Y13嘌呤受體刺激劑,諸如CER-209; PDE 3/4抑制劑,諸如泰魯斯特(MN-001); PDE 5抑制劑,諸如西地那非或MSTM-102; PDGF受體β調節劑,諸如BOT-191或BOT-509; 肽基-脯胺醯基順式-反式異構酶抑制劑,諸如CRV-431 (CPI-432-32)、NVP-018或NV-556 (NVP-025); 苯丙胺酸羥化酶刺激劑,諸如HepaStem; PPAR促效劑(包括PPAR α促效劑、PPAR α/δ促效劑、PPAR α/δ/γ促效劑、PPAR δ促效劑),諸如艾拉菲諾(elafibranor) (GFT-505)、MBX-8025、氘化吡格列酮R-對映異構體、吡格列酮、DRX-065、沙格列紮(saroglitazar)或IVA-337;PPAR α促效劑,諸如氯貝酸鋁(aluminum clofibrate)、苯紮貝特(bezafibrate)、環丙貝特(ciprofibrate)、膽鹼非諾貝特(choline fenofibrate)、克利貝特(clinofibrate)、氯貝特(clofibrate)、氯貝胺(clofibride)、非諾貝特(fenofibrate)、吉非羅齊(gemfibrozil)、佩馬貝特(pemafibrate)、氯煙貝特(ronifibrate)、雙貝特(simfibrate)、ω-3脂肪酸(魚油,例如二十碳五烯酸乙酯(Vascepa® )或二十二碳六烯酸)、匹立尼酸(pirinixic acid)、GW409544、AZ 242、LY518674、NS-220、AVE8134、BMS-711939、阿格列紮(aleglitazar)、穆拉格列紮(muraglitzar)或沙格列紮; PPAR α/δ促效劑,諸如艾拉菲諾; PPAR α/δ/γ促效劑,諸如拉尼菲諾(lanifibranor); PPAR δ促效劑,諸如塞拉德帕(seladelpar); 蛋白酶活化受體-2拮抗劑,諸如PZ-235; 蛋白激酶調節劑,諸如CNX-014; ρ相關蛋白激酶(ROCK)抑制劑,諸如REDX-10178 (REDX-10325)或KD-025; 胺脲敏感性胺氧化酶/血管黏附蛋白-1 (SSAO/VAP-1)抑制劑,諸如PXS-4728A; S-硝基麩胱甘肽還原酶(GSNOR)酶抑制劑,諸如SL-891; 鈉葡萄糖轉運體-2 (SGLT2)抑制劑,諸如伊格列淨(ipragliflozin)、依碳酸瑞格列淨(remogliflozin etabonate)、埃格列淨(ertugliflozin)、達格列淨(dapagliflozin)或索格列淨(sotagliflozin); SREBP轉錄因子抑制劑,諸如CAT-2003或MDV-4463; 硬脂醯基CoA去飽和酶-1抑制劑,諸如阿雷美羅(aramchol); 甲狀腺激素受體(THR) β促效劑,諸如瑞斯蒙催(MGL-3196)、MGL-3745或VK-2809; TLR-2/TLR-4拮抗劑,諸如VB-201 (CI-201); TLR-4拮抗劑,諸如JKB-121; 酪胺酸激酶受體調節劑,諸如CNX-025或GFE-2137 (重新設置硝唑尼特(repurposed nitazoxanide)); GPCR調節劑,諸如CNX-023; 核激素受體調節劑,諸如Px-102; 黃嘌呤氧化酶/尿酸鹽陰離子交換劑1(URAT1)抑制劑,諸如RLBN-1001、RLBN-1127;及 連蛋白抑制劑,諸如乙酸羅拉唑肽(lorazotide acetate) (INN-202)。Non-limiting examples of the one or more additional therapeutic agents include ACE inhibitors, such as enalapril; acetyl CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382, or PF-05221304; acetyl CoA carboxylase/diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341; acetaldehyde dehydrogenase inhibitors, such as ADX-629; adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, or CGS21680; adiponectin receptor agonists, such as ADP-355 or ADP-399; amylin/calcitonin receptor agonists, such as KBP-042 or KBP-089; AMP-activated protein kinase stimulators, such as PXL-770 or O-304; AMP kinase activators/ATP citrate lyase inhibitors, such as bempedoic acid (ETC-1002, ESP-55016); AMP-activated protein kinase/endothelial nitric oxide synthase/NAD-dependent deacetylase longevity protein-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil); androgen receptor agonists, such as LPCN-1144; angiotensin II AT-1 receptor antagonists, such as irbesartan; angiopoietin-associated protein-3 inhibitors, such as IONIS-ANGPTL3-LRx; autocrine motor factor inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877; Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428); Bax protein stimulators, such as CBL-514; Bioactive lipids, such as DS-102; Cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab, GWP-42004, REV-200 or CRB-4001; Apoptotic protease inhibitors, such as emricasan; Pan cathepsin B inhibitors, such as VBY-376; Pan cathepsin inhibitors, such as VBY-825; CCR2/CCR5 chemotherapeutic hormone antagonists, such as cenicriviroc, maraviroc, CCX-872 or WXSH-0213; CCR2 chemotherapeutic hormone antagonists, such as propagermanium; CCR2 chemotherapeutic hormone/angiotensin II AT-1 receptor antagonists, such as DMX-200 or DMX-250; CCR2/CCR5 chemotherapeutic hormone antagonists and FXR agonists, such as LJC-242 (tropifexor + cenivriviroc); CCR3 chemotherapeutic hormone antagonists, such as bertilimumab; Chloride channel stimulators, such as cobiprostone or lubiprostone; CD3 antagonists, such as NI-0401 (foralumab); CXCR4 chemokine antagonists, such as AD-214; diglycerol acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; diglycerol O-acyltransferase 1 (DGAT1)/cytochrome P450 2E1 inhibitors (CYP2E1), such as SNP-610; diglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx or PF-06865571; Dipeptidyl peptidase IV inhibitors, such as linagliptin or evogliptin; Eosin ligand inhibitors, such as bacitrazumab or CM-101; Extracellular matrix protein regulators, such as CNX-024; Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228; Farnesoid X receptor (FXR)/G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767; Fatty acid synthase inhibitors, such as TVB-2640; FGF receptor agonists/clotrol beta stimulators, such as BFKB-8488A (RG-7992); Fibroblast growth factor 19 (rhFGF19)/cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282; Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, B-1344, or BMS-986036; Fibroblast growth factor 21 (FGF-21)/glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241) or AKR-001; Fish oil compositions, such as eicosapentaenoic acid ethyl ester (Vascepa ® ); Galectin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300) or GB1211 (Gal-400); Glucagon-like peptide 1 receptor (GLP1R) agonists, such as AC-3174, liraglutide, cofactor (MEDI-0382), exenatide, SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718 or semaglutide; Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant); Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001; G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009 or INT-777; Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201; HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin; Hypoxia-inducing factor-2α inhibitors, such as PT-2567; IL-10 agonists, such as peg-ilodecakin; Ileal sodium bile acid symporter inhibitors, such as odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, or eloxibat (A-3309); Insulin sensitizers, such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211, or ETI-101; Insulin ligands/insulin receptor agonists, such as ORMD-0801; Integrin antagonists, such as IDL-2965; IL-6 receptor agonists, such as KM-2702; Ketokinase (KHK) inhibitors, such as PF-06835919; β-Clark (KLB)-FGF1c agonists, such as MK-3655 (NGM-313); 5-lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102); Lipoprotein lipase inhibitors, such as CAT-2003; LPL gene stimulators, such as alipogene tiparvovec; Liver X receptor (LXR) modulators, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, or SR-9238; Lysophosphatidic acid-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, or KI-16198; Lysamidyl oxidase homolog 2 inhibitors, such as simtuzumab or PXS-5382A (PXS-5338); Macrophage mannose receptor 1 modulators, such as tilmanocept-Cy3 (Tc 99m temanothi); membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201; MEKK-5 protein kinase (ASK-1) inhibitors, such as GS-4997, SRT-015 or GS-444217, GST-HG-151; MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158); methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839 or ZN-1345; methyl CpG binding protein 2 regulators, such as ethylamine; mitochondrial decoupling agents, such as 2,4-dinitrophenol or HU6; Mixed spectrum kinase-3 inhibitors, such as URMC-099-C; Myelin alkaline protein stimulators, such as olesoxime; NADPH oxidase 1/4 inhibitors, such as GKT-831 or APX-311; Niacin receptor 1 agonists, such as ARI-3037MO; Nitazoxinide; NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, or JT-194 (JT-349); Nuclear receptor modulators, such as DUR-928 (DV-928); P2X7 purine receptor modulators, such as SGM-1019; P2Y13 purine receptor stimulators, such as CER-209; PDE 3/4 inhibitors, such as Taluster (MN-001); PDE 5 inhibitors, such as sildenafil or MSTM-102; PDGF receptor β modulators, such as BOT-191 or BOT-509; Peptidyl-prolinyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018 or NV-556 (NVP-025); Phenylalanine hydroxylase stimulators, such as HepaStem; PPAR agonists (including PPAR α agonists, PPAR α/δ agonists, PPAR α/δ/γ agonists, PPAR δ agonists), such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, or IVA-337; PPAR α agonists, such as aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, ronifibrate, simfibrate, omega-3 fatty acids (fish oils, such as eicosapent ethyl (Vascepa ® ) or docosahexaenoic acid), pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitzar, or saxaglitazar; PPAR alpha/delta agonists, such as elafinor; PPAR α/δ/γ agonists, such as lanifenor; PPAR δ agonists, such as seladelpar; Protease-activated receptor-2 antagonists, such as PZ-235; Protein kinase modulators, such as CNX-014; Rho-related protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325) or KD-025; Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) inhibitors, such as PXS-4728A; S-nitroglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891; Sodium glucose transporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, or sotagliflozin; SREBP transcription factor inhibitors, such as CAT-2003 or MDV-4463; Stearoyl CoA desaturase-1 inhibitors, such as aramchol; Thyroid hormone receptor (THR) beta agonists, such as rismond (MGL-3196), MGL-3745, or VK-2809; TLR-2/TLR-4 antagonists, such as VB-201 (CI-201); TLR-4 antagonists, such as JKB-121; tyrosine kinase receptor modulators, such as CNX-025 or GFE-2137 (repurposed nitazoxanide); GPCR modulators, such as CNX-023; nuclear hormone receptor modulators, such as Px-102; xanthine oxidase/urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and zonulin inhibitors, such as lorazotide acetate (INN-202).
一或多種額外治療劑之額外非限制性實例包括: ACE抑制劑,諸如貝那普利(benazepril)、咪達普利(imidapril); 腺苷A3受體拮抗劑,諸如FM-101; 阿德羅平(Adropin)刺激劑,諸如RBT-2; 白蛋白調節劑,諸如SYNT-002; 醛固酮/鹽皮質激素受體拮抗劑,諸如MT-3995; 同種異體骨髓源性間葉基質細胞療法,諸如ORBCEL-M; 同種異體擴增脂肪源性幹細胞療法,諸如Elixcyte™; AMP活化蛋白激酶刺激劑/前蛋白轉化酶PC9抑制劑,諸如O-304; AMP活化蛋白激酶刺激劑,諸如DZCY-01、MK-8722、PXL-770; 血管收縮素II AT-1受體/CCR2趨化激素拮抗劑,諸如DMX-200; 血管收縮素II AT-2受體促效劑,諸如MOR-107、依貝沙坦; 血管收縮素II受體拮抗劑,諸如洛沙坦(losartan); 血管收縮素原配位體抑制劑,諸如ALN-AGT; 抗C1抗體,諸如BIVV-009 (蘇替莫單抗(sutimlimab)); 抗CB1抗體,諸如GFB-024; 抗CX3CR1奈米抗體,諸如BI-655088; 抗IL-6抗體,諸如COR-001; 抗VEGF-B抗體,諸如CSL-346; APOA1基因刺激劑/含溴域之蛋白質2/含溴域之蛋白質4抑制劑,諸如阿貝他酮(apabetalone); 骨形態生成蛋白-7配位體調節劑,諸如BMP-7; 鈣通道抑制劑,諸如TBN (消痛𠯤(xiaotongqin)); 大麻素CB1受體拮抗劑,諸如JNJ-2463; CB1反向促效劑,諸如CRB-4001; 凝乳酶抑制劑,諸如氟拉司他(fulacimstat) (BAY-1142524); 環加氧酶1抑制劑,諸如GLY-230; 環加氧酶2/環氧化物水解酶抑制劑,諸如COX-2/可溶性環氧化物水解酶; 細胞色素P450 11B2抑制劑,諸如醛固酮合成酶抑制劑; 外核苷酸焦磷酸酶-PDE-2抑制劑,諸如BLD-0409; 內皮素ET-A/內皮素ET-B受體拮抗劑,諸如阿普羅西替坦(aprocitentan); 腸肽酶抑制劑,諸如SCO-792; 紅血球生成素受體拮抗劑,諸如EPO-018B; 類法尼醇X受體促效劑,諸如LMB-763; FGF/PDGF/β受體拮抗劑/p38 MAP激酶抑制劑,諸如吡非尼酮(pirfenidone); GHR/IGF1基因抑制劑,諸如阿特西多森鈉(atesidorsen sodium); GPR40促效劑/GPR84拮抗劑,諸如PBI-4050; G蛋白β次單元抑制劑,諸如加利恩(galleon); G蛋白偶聯受體84調節劑,諸如PBI-4425; 生長激素配位體/生長激素受體促效劑,諸如Jintropin AQ™; 生長激素受體促效劑,諸如LAT-8881; 鳥苷酸環化酶受體促效劑/鳥苷酸環化酶刺激劑,諸如帕利西喹(praliciguat); 鳥苷酸環化酶刺激劑,諸如MRL-001、潤卡西哌(runcaciguat); 血基質加氧酶1調節劑,諸如RBT-1; HIF脯胺醯基羥化酶抑制劑,諸如TRGX-154; 胰島素敏化劑/激肽釋放素1調節劑,諸如DM-199; 整合素α-V/β-3拮抗劑,諸如VPI-2690B; 介白素33配位體抑制劑,諸如MEDI-3506; 類Kelch ECH相關蛋白1調節劑/核紅血球系2-相關因子2刺激劑,諸如SFX-01; LDHA基因抑制劑,諸如尼多西蘭(nedosiran); 5-脂肪加氧酶活化蛋白抑制劑,諸如AZD-5718; 溶血磷脂酸-1受體拮抗劑,諸如BMS-002、EPGN-696; 基質細胞外磷酸醣蛋白調節劑/磷調因子(Phosphatonin)受體促效劑,諸如TPX-200; MEKK-5蛋白激酶抑制劑,諸如司隆色替(selonsertib); 膜銅胺氧化酶抑制劑,諸如UD-014; 中期因子配位體抑制劑,諸如CAB-101; 鹽皮質激素受體拮抗劑,諸如AZD-9977、埃沙西林酮(esaxerenone)、非瑞酮(finerenone)、KBP-5074; 肌凝蛋白2抑制劑,諸如DeciMab™; NADPH氧化酶1抑制劑/NADPH氧化酶4抑制劑,諸如西他那昔布(setanaxib); NADPH氧化酶抑制劑,諸如APX-115; NK1受體拮抗劑/類鴉片受體κ促效劑/類鴉片受體μ拮抗劑,諸如AV-104; 核紅血球系2-相關因子2刺激劑/TGF β配位體抑制劑,諸如CU01-1001; 核因子κ B抑制劑,諸如美富尼酮(mefunidone)、甲基巴多索隆(bardoxolone methyl)(NSC-713200); PDE 4抑制劑,諸如ART-648、PCS-499; PDGF受體β調節劑,諸如BOT-191; PDGF/VEGF受體拮抗劑,諸如ANG-3070; PR84拮抗劑/GPR40 (FFAR1)/GPR120 (FFAR4)促效劑/及過氧化體增殖物活化之受體之部分活化劑(PPAR),諸如PBI-4547; PRKAA2基因刺激劑/AMPK活化劑,諸如PF-06679142、PF-06685249; 前列環素(PGI2)促效劑,諸如YS-1402; 蛋白C活化劑/醣蛋白Ib (GPIb)拮抗劑,諸如AB-002; 蛋白NOV同系物調節劑,諸如BLR-200; 蛋白酪胺酸磷酸酶-1B抑制劑,諸如MSI-1436; 反應性含氧物種調節劑抑制劑,諸如SUL-121; 腎素抑制劑,諸如鹽酸伊馬利克倫(imarikiren hydrochloride); ρ相關蛋白激酶2抑制劑,諸如ANG-4201、RXC-007; 鈉葡萄糖轉運體-2抑制劑,諸如卡格列淨(canagliflozin)、達格列淨丙二醇、恩格列淨(empagliflozin); 凝血脂素A2受體拮抗劑/凝血脂素合成抑制劑,諸如SER-150; 組織轉麩醯胺酸酶抑制劑,諸如ZED-1227; TRP陽離子通道C5抑制劑,諸如GFB-887; TRP陽離子通道C6抑制劑,諸如ALGX-2224; 細胞黏附分子抑制劑,諸如糖苷細菌黏附素拮抗劑; 尿酸鹽陰離子交換劑1 (URAT1)/SLC22A12抑制劑,諸如維立諾雷(verinurad) (RDEA3170); VIP 1/VIP 2受體促效劑,諸如LBT-3627;及 黃嘌呤氧化酶抑制劑,諸如TMX-049、TMX-049DN。Additional non-limiting examples of one or more additional therapeutic agents include: ACE inhibitors, such as benazepril, imidapril; Adenosine A3 receptor antagonists, such as FM-101; Adropin stimulants, such as RBT-2; Albumin regulators, such as SYNT-002; Aldosterone/corticosteroid receptor antagonists, such as M T-3995; Allogeneic bone marrow-derived mesenchymal cell therapy, such as ORBCEL-M; Allogeneic expanded adipose-derived stem cell therapy, such as Elixcyte™; AMP-activated protein kinase stimulators/proprotein convertase PC9 inhibitors, such as O-304; AMP-activated protein kinase stimulators, such as DZCY-01, MK-8722, PXL-770; Angiotensin II AT-1 receptor/CCR2 chemokine antagonists, such as DMX-200; Angiotensin II AT-2 receptor agonists, such as MOR-107, irbesartan; Angiotensin II receptor antagonists, such as losartan; Angiotensin proligand inhibitors, such as ALN-AGT; Anti-C1 antibodies, such as BIVV-009 (sutimlimab); Anti-CB1 antibodies, such as GFB-024; Anti-CX3CR1 nanoantibodies, such as BI-655088; Anti-IL-6 antibodies, such as COR-001; Anti-VEGF-B antibodies, such as CSL-346; APOA1 gene stimulators/bromodomain-containing protein 2/bromodomain-containing protein 4 inhibitors, such as apabetalone; Bone morphogenetic protein-7 ligand regulators, such as BMP-7; Calcium channel inhibitors, such as TBN (xiaotongqin); Cannabinoid CB1 receptor antagonists, such as JNJ-2463; CB1 reverse agonists, such as CRB-4001; Chonomycin inhibitors, such as fulacimstat (BAY-1142524); Cyclooxygenase 1 inhibitors, such as GLY-230; Cyclooxygenase 2/epoxide hydrolase inhibitors, such as COX-2/soluble epoxide hydrolase; Cytochrome P450 11B2 inhibitors, such as aldosterone synthase inhibitors; Exonucleotide pyrophosphatase-PDE-2 inhibitors, such as BLD-0409; Endothelin ET-A/endothelin ET-B receptor antagonists, such as aprocitentan; Enteropepeptidase inhibitors, such as SCO-792; Erythropoietin receptor antagonists, such as EPO-018B; Farnesoid X receptor agonists, such as LMB-763; FGF/PDGF/β receptor antagonists/p38 MAP kinase inhibitors, such as pirfenidone; GHR/IGF1 gene inhibitors, such as atesidorsen sodium sodium); GPR40 agonists/GPR84 antagonists, such as PBI-4050; G protein β subunit inhibitors, such as galleon; G protein-coupled receptor 84 modulators, such as PBI-4425; Growth hormone ligands/Growth hormone receptor agonists, such as Jintropin AQ™; Growth hormone receptor agonists, such as LAT-8881; Guanylate cyclase receptor agonists/Guanylate cyclase stimulators, such as praliciguat; Guanylate cyclase stimulators, such as MRL-001, runcaciguat; Hydrogen stromal oxygenase 1 modulators, Such as RBT-1; HIF prolinyl hydroxylase inhibitors, such as TRGX-154; Insulin sensitizers/kinin release 1 modulators, such as DM-199; Integrin α-V/β-3 antagonists, such as VPI-2690B; Interleukin 33 ligand inhibitors, such as MEDI-3506; Kelch-like ECH-related protein 1 regulator/erythroid lineage 2-related factor 2 stimulator, such as SFX-01; LDHA gene inhibitor, such as nedosiran; 5-lipoxygenase activating protein inhibitor, such as AZD-5718; Lysophosphatidic acid-1 receptor antagonist, such as BMS-002, EPGN-696; Matrix extracellular phosphatidylcholine regulator/phosphatonin receptor agonist, such as TPX-200; MEKK-5 protein kinase inhibitor, such as selonsertib; Membrane copper amine oxidase inhibitor, such as UD-014; Mesophase factor =Subligand inhibitors, such as CAB-101; Oligocortin receptor antagonists, such as AZD-9977, esaxerenone, finerenone, KBP-5074; Myosin 2 inhibitors, such as DeciMab™; NADPH oxidase 1 inhibitors/NADPH oxidase 4 inhibitors, such as setanaxib; NADPH oxidase inhibitors, such as APX-115; NK1 receptor antagonists/opioid receptor κ agonists/opioid receptor μ antagonists, such as AV-104; TGF-β2 stimulators β-ligand inhibitors, such as CU01-1001; Nuclear factor κB inhibitors, such as mefunidone, bardoxolone methyl (NSC-713200); PDE 4 inhibitors, such as ART-648, PCS-499; PDGF receptor β-modulators, such as BOT-191; PDGF/VEGF receptor antagonists, such as ANG-3070; PR84 antagonists/GPR40 (FFAR1)/GPR120 (FFAR4) agonists/and partial activators of peroxisome proliferator-activated receptors (PPAR), such as PBI-4547; PRKAA2 gene stimulators/AMPK activators, such as PF-06679142, PF-06685249; Prostacyclin (PGI2) agonists, such as YS-1402; Protein C activators/glycoprotein Ib (GPIb) antagonists, such as AB-002; Protein NOV homolog regulators, such as BLR-200; Protein tyrosine phosphatase-1B inhibitors, such as MSI-1436; Reactive oxygen species regulator inhibitors, such as SUL-121; Nephrin inhibitors, such as imarikiren hydrochloride; Rho-related protein kinase 2 inhibitors, such as ANG-4201, RXC-007; Sodium glucose transporter-2 inhibitors, such as canagliflozin, dapagliflozin propylene glycol, empagliflozin; Thrombin A2 receptor antagonists/thrombin Tissue transglutaminase inhibitors, such as ZED-1227; TRP cation channel C5 inhibitors, such as GFB-887; TRP cation channel C6 inhibitors, such as ALGX-2224; Cell adhesion molecule inhibitors, such as glycosidic bacterial adhesin antagonists; Urate anion exchanger 1 (URAT1)/SLC22A12 inhibitors, such as verinurad (RDEA3170); VIP 1/VIP 2 receptor agonists, such as LBT-3627; and Xanthine oxidase inhibitors, such as TMX-049, TMX-049DN.
在一些實施例中,一或多種額外治療劑係選自A-4250、AC-3174、乙醯水楊酸、AK-20、阿利潑金、AMX-342、AN-3015、阿雷美羅、ARI-3037MO、天冬胺酸-8232、AZD-2693、柏替利木單抗、無水甜菜鹼、BI-1467335、BMS-986036、BMS-986171、BMT-053011、BOT-191、BTT-1023、CAT-2003、森尼韋若、CBW-511、CER-209、CF-102、CGS21680、CNX-014、CNX-023、CNX-024、CNX-025、科普斯酮、考來維侖(colesevelam)、達格列淨、DCR-LIV1、氘化吡格列酮R-對映異構體、2,4-二硝基苯酚、DRX-065、DS-102、DUR-928、EDP-305、艾拉菲諾(GFT-505)、恩利卡生、依那普利、埃格列淨、依格列汀、F-351、氟斯特酮(fluasterone)(ST-002)、FT-4101、GKT-831、GNF-5120、GRI-0621、GR-MD-02、GS-300、GS-4997、GS-9674、HTD-1801、HST-202、HST-201、氫氯噻𠯤、二十酯(PRC-4016)、二十碳五烯酸乙酯、IMM-124-E、INT-767、INV-240、IONIS-DGAT2Rx、伊格列淨、依貝沙坦、丙帕鍺、IVA-337、JKB-121、KB-GE-001、KBP-042、KD-025、M790、M780、M450、二甲雙胍、西地那非、LC-280126、利格列汀、利拉魯肽、LJN-452 (曲匹氟索)、LM-011、LM-002 (CVI-LM-002)、LMB-763、LYN-100、MBX-8025、MDV-4463、巰乙胺、MGL-3196、MGL-3745、MP-301、MSDC-0602K、納馬珠單抗、NC-101、NDI-010976、ND-L02-s0201 (BMS-986263)、NGM-282、NGM-313、NGM-386、NGM-395、NP-160、降熊去氧膽酸、NVP-022、O-304、奧貝膽酸(OCA)、25HC3S、奧利索西、PAT-505、PAT-048、PBI-4547、peg-伊洛白介素、吡格列酮、吡非尼酮、PRI-724、PX20606、Px-102、PX-L603、PX-L493、PXS-4728A、PZ-235、RDX-009、依碳酸瑞格列淨、RG-125(AZD4076)、RPI-500、沙格列讓(saroglitazar)、索馬魯肽、辛圖珠單抗、索利黴素、索格列淨、士他汀(阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、羅素他汀、辛伐他汀)、共生、TCM-606F、TEV-45478、TQA-3526、泰魯斯特(MN-001)、TLY-012、TRX-318、TVB-2640、UD-009、熊去氧膽酸、VBY-376、VBY-825、VK-2809、維莫德吉(vismodegib)、沃立昔巴(volixibat)乙醇鉀水合物(SHP-626)、VVP-100X、WAV-301、WNT-974、XRx-117、ZGN-839、ZG-5216、ZSYM-008及ZYSM-007。In some embodiments, the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, alipoquinone, AMX-342, AN-3015, alemiro, ARI-3037MO, aspartate-8232, AZD-2693, betilimumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, B TT-1023, CAT-2003, Senivero, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, coprestone, colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, Eraphinol (GFT-505), Enricasan, Enalapril, Eragliptin, Emigliptin, F-351, Fluasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, Hydrochlorothiazide, Eicosyl ester (PRC-4016), icosapent ethyl, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliptin, irbesartan, propagation, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452 (Tripiflux), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, ethylamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, nablizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-160, nordeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olisoxime, PAT-505, PAT-048, PBI-4547, peg-iloleukin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, repaglinide etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab, Solisomycin, solafloxacin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), symbiotic, TCM-606F, TEV-45478, TQA-3526, telust (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, volixibat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008 and ZYSM-007.
在一些實施例中,本文所提供之方法及醫藥組合物包括治療有效量之凋亡信號調節激酶1 (ASK1)抑制劑及治療有效量之LPAR1拮抗劑,其中LPAR1拮抗劑為本文所提供之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)化合物或其醫藥學上可接受之鹽。In some embodiments, the methods and pharmaceutical compositions provided herein include a therapeutically effective amount of an apoptosis signal-regulating kinase 1 (ASK1) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) provided herein, or a pharmaceutically acceptable salt thereof.
在本文所揭示之方法及醫藥組合物的一些實施例中,ASK1抑制劑為GS-4997(司隆色替(selonsertib),SEL)。In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (selonsertib, SEL).
ASK1抑制劑可以使用熟習此項技術者已知之方法,諸如描述於U.S. 2007/0276050、U.S. 2011/0009410及U.S. 2013/0197037中之彼等方法來合成及表徵。ASK1 inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in U.S. 2007/0276050, U.S. 2011/0009410, and U.S. 2013/0197037.
在一些實施例中,本文所提供之方法及醫藥組合物包括治療有效量之乙醯基-CoA羧化酶(ACC)抑制劑及治療有效量之LPAR1拮抗劑,其中該LPAR1拮抗劑為本文所提供之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)或(IIi)化合物或其醫藥學上可接受之鹽。In some embodiments, the methods and pharmaceutical compositions provided herein include a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) provided herein, or a pharmaceutically acceptable salt thereof.
在本文所揭示之方法及醫藥組合物的一些實施例中,ACC抑制劑為GS-0976 (菲索科司他,FIR)。In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (fisocostat, FIR).
ACC抑制劑可以使用熟習此項技術者已知之方法,諸如描述於美國專利第9,453,026號及美國專利第10,183,951號中者來合成及表徵。ACC inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in U.S. Patent No. 9,453,026 and U.S. Patent No. 10,183,951.
在一些實施例中,本文所提供之方法及組合物包括治療有效量之PPAR促效劑(例如PPAR α促效劑、PPAR α/δ促效劑、PPAR α/δ/γ促效劑、PPAR δ促效劑)或魚油,治療有效量之乙醯基CoA羧化酶(ACC)抑制劑,諸如GS-0976(菲索科司他,FIR)及治療有效量之LPAR1拮抗劑,其中該LPAR1拮抗劑為本文所提供之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽。在一些實施例中,PPAR促效劑為PPAR α促效劑。在一些實施例中,PPAR α促效劑係選自:氯貝酸鋁、苯紮貝特、環丙貝特、膽鹼非諾貝特、克利貝特、氯貝特、氯貝胺、非諾貝特、吉非羅齊、佩馬貝特、氯煙貝特、雙貝特、匹立尼酸、GW409544、AZ 242、LY518674、NS-220、AVE8134、BMS-711939、阿格列紮、穆拉格列紮及沙格列紮。在一些實施例中,PPAR促效劑(例如PPAR α促效劑)為纖維酸酯(fibrate)。在一些實施例中,PPAR促效劑(例如PPAR α促效劑)為非諾貝特。在一些實施例中,PPAR促效劑為PPAR α/δ促效劑(例如艾拉菲諾)。在一些實施例中,PPAR促效劑為PPAR α/δ/γ促效劑(例如拉尼菲諾)。在一些實施例中,PPAR促效劑為PPAR δ促效劑(例如塞拉德帕)。在一些實施例中,魚油為ω-3脂肪酸或二十二碳六烯酸。在一些實施例中,魚油為二十碳五烯酸乙酯(例如Vascepa® )。In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a PPAR agonist (e.g., a PPAR α agonist, a PPAR α/δ agonist, a PPAR α/δ/γ agonist, a PPAR δ agonist) or fish oil, a therapeutically effective amount of an acetyl CoA carboxylase (ACC) inhibitor, such as GS-0976 (fisocostat, FIR), and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is a PPAR alpha agonist. In some embodiments, the PPAR alpha agonist is selected from: aluminum clofibrate, benzafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, permafibrate, clofibrate, bifibrate, pironic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitza, mulaglitza and saxaglitza. In some embodiments, the PPAR agonist (e.g., PPAR alpha agonist) is a fibrate. In some embodiments, the PPAR agonist (e.g., a PPAR alpha agonist) is fenofibrate. In some embodiments, the PPAR agonist is a PPAR alpha/delta agonist (e.g., elafinol). In some embodiments, the PPAR agonist is a PPAR alpha/delta/gamma agonist (e.g., lanifino). In some embodiments, the PPAR agonist is a PPAR delta agonist (e.g., seradepa). In some embodiments, the fish oil is omega-3 fatty acids or docosahexaenoic acid. In some embodiments, the fish oil is eicosapentaenoic acid ethyl ester (e.g., Vascepa ® ).
在一些實施例中,本文所提供之方法及組合物包括治療有效量之類法尼醇X受體(FXR)促效劑及治療有效量之LPAR1拮抗劑,其中該LPAR1拮抗劑為本文所提供之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽。In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a farnesoid X receptor (FXR) agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) provided herein, or a pharmaceutically acceptable salt thereof.
在本文所揭示之方法及醫藥組合物的一些實施例中,FXR促效劑為GS-9674 (希勒氟索(cilofexor),CILO)。In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).
在本文所揭示之方法及醫藥組合物的一些實施例中,FXR促效劑為具有以下結構之化合物: 或其醫藥學上可接受之鹽。In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the following structure: or a pharmaceutically acceptable salt thereof.
在一些實施例中,本文所提供之方法及組合物包括治療有效量之GLP-1受體促效劑及治療有效量之LPAR1拮抗劑,其中該LPAR1拮抗劑為式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽。在一些實施例中,GLP-1受體促效劑為利拉魯肽或索馬魯肽。在一些實施例中,GLP-1受體促效劑為索馬魯肽。In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a GLP-1 receptor agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or semaglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide.
在一些實施例中,本文所提供之方法及組合物包括治療有效量之TGFβ拮抗劑及治療有效量之LPAR1拮抗劑,其中該LPAR1拮抗劑為本文所提供之式(I)、(Ia)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)、(IIl)、(IIm)、(IIn)或(IIo)化合物或其醫藥學上可接受之鹽。在一些實施例中,TGFβ拮抗劑為TGFβ特異性抗體。TGFβ特異性抗體可以使用熟習此項技術者已知之方法,諸如描述於PCT國際申請公開案第WO 2018/129329號及美國專利第9,518,112號中之彼等方法來製備及表徵。在一些實施例中,TGFβ拮抗劑結合至TGFβ潛伏相關肽(LAP),例如TGFβ 1-LAP。TGFβ 1-LAP特異性抗體可使用熟習此項技術者已知之方法,諸如描述於美國專利第8,198,412號或美國專利第10,017,567號中之彼等方法來製備及表徵。在一些實施例中,TGFβ拮抗劑以與上下文無關之方式(例如,與TGFβ在特定組織或器官中之呈現無關)結合於TGFβ (例如,TGFβ 1)。在一些實施例中,TGFβ拮抗劑以與上下文有關之方式結合於TGFβ (TGFβ 1)。在一些實施例中,TGFβ拮抗劑阻斷位於細胞外基質中(例如,肝臟之結締組織中)的潛伏TGFβ (例如,潛伏TGFβ 1)之活化。在一些實施例中,TGFβ拮抗劑阻斷位於胸腺、淋巴結或腫瘤微環境中(例如在患有肝癌之患者中)之潛伏TGFβ(例如潛伏TGFβ 1)之活化。在一些實施例中,TGFβ拮抗劑藉由潛伏TGFβ結合蛋白(LTBP)阻斷潛伏TGFβ(例如潛伏TGFβ 1)之活化。在一些實施例中,如例如美國專利第10,000,572號中所描述,TGFβ拮抗劑藉由糖蛋白-A重複優先顯性蛋白質(GARP)阻斷潛伏TGFβ(例如潛伏TGFβ 1)之活化。在一些實施例中,TGFβ拮抗劑為ARGX-115。在一些實施例中,TGFβ拮抗劑為特異性結合至LAP-TGFβ錯合物之抗潛伏相關肽(LAP)抗體。在一些實施例中,抗LAP抗體特異性結合於例如肝臟中之結締組織之細胞外基質(ECM)中的LAP-TGFβ錯合物。在一些實施例中,抗LAP抗體例如在腫瘤微環境中在某些免疫抑制性細胞類型,諸如調節T細胞(Treg)、腫瘤相關巨噬細胞或骨髓衍生之抑制細胞之表面上特異性結合於LAP-TGFβ錯合物。在一些實施例中,抗LAP抗體為TLS-01抗體。在一些實施例中,抗LAP抗體在任何情形下特異性結合至LAP-TGFβ錯合物。在一些實施例中,抗LAP抗體為TLS-02抗體。在一些實施例中,TGFβ拮抗劑包含TGFβ受體。在一些實施例中,TGFβ拮抗劑為TGFβ受體-Fc融合蛋白。在一些實施例中,TGFβ拮抗劑為包含TGFβ受體之抗體。包含可以適用於與本文所提供之組合物及方法結合之TGFβ受體的TGFβ拮抗劑已描述於例如PCT國際公開案第WO 2019/113123 A1號及第WO 2019/113464 A1號中。In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a TGFβ antagonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the TGFβ antagonist is a TGFβ specific antibody. TGFβ specific antibodies can be prepared and characterized using methods known to those skilled in the art, such as those described in PCT International Application Publication No. WO 2018/129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist binds to a TGFβ latent associated peptide (LAP), such as TGFβ 1-LAP. TGFβ 1-LAP specific antibodies can be prepared and characterized using methods known to those skilled in the art, such as those described in U.S. Patent No. 8,198,412 or U.S. Patent No. 10,017,567. In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ 1) in a context-independent manner (e.g., independent of the presentation of TGFβ in a particular tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (TGFβ 1) in a context-dependent manner. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ 1) located in the extracellular matrix (e.g., in the connective tissue of the liver). In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ 1) located in the thymus, lymph nodes, or tumor microenvironment (e.g., in patients with liver cancer). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ 1) by latent TGFβ binding protein (LTBP). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ 1) by glycoprotein-A repeat prioritization protein (GARP), as described, for example, in U.S. Patent No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is an anti-latency associated peptide (LAP) antibody that specifically binds to a LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to a LAP-TGFβ complex in the extracellular matrix (ECM) of connective tissue, for example, in the liver. In some embodiments, the anti-LAP antibody specifically binds to a LAP-TGFβ complex, for example, on the surface of certain immunosuppressive cell types, such as regulatory T cells (Treg), tumor-associated macrophages, or bone marrow-derived suppressor cells in the tumor microenvironment. In some embodiments, the anti-LAP antibody is a TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to a LAP-TGFβ complex under any circumstances. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist comprises a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. TGFβ antagonists comprising a TGFβ receptor that can be used in conjunction with the compositions and methods provided herein have been described, for example, in PCT International Publication Nos. WO 2019/113123 A1 and WO 2019/113464 A1.
在一些實施例中,本文所提供之方法及組合物包括治療有效量之LPAR1拮抗劑及選自以下之治療有效量之額外治療劑:ACE抑制劑、腺苷A3受體拮抗劑、阿德羅平刺激劑、白蛋白調節劑、醛固酮拮抗劑、AMP活化蛋白激酶刺激劑、血管收縮素II AT-2受體促效劑、血管收縮素II受體拮抗劑、血管收縮素原配位體抑制劑、APOA1基因刺激劑、脂蛋白元L1調節劑、骨形態生成蛋白-7配位體調節劑、含溴域之蛋白質2抑制劑、含溴域之蛋白質4抑制劑、鈣通道抑制劑、大麻素CB1受體拮抗劑、CB1反向促效劑、CCR2趨化激素拮抗劑、凝乳酶抑制劑、補體C1子組分抑制劑、CX3CR1趨化激素拮抗劑、環加氧酶1抑制劑、環加氧酶2抑制劑、細胞色素P450 11B2抑制劑、外核苷酸焦磷酸酶-PDE-2抑制劑、內皮素ET-A受體拮抗劑、內皮素ET-B受體拮抗劑、腸肽酶抑制劑、環氧化物水解酶抑制劑、紅血球生成素受體拮抗劑、類法尼醇X受體促效劑、FGF受體拮抗劑、游離脂肪酸受體1促效劑、GHR基因抑制劑、醣蛋白Ib (GPIb)拮抗劑、GPR40促效劑、GPR84拮抗劑、G蛋白β次單元抑制劑、G蛋白偶聯受體120促效劑、G蛋白偶聯受體84調節劑、生長激素配位體、生長激素受體促效劑、鳥苷酸環化酶受體促效劑、鳥苷酸環化酶刺激劑、血基質加氧酶1調節劑、HIF脯胺醯基羥化酶抑制劑、IGF1基因抑制劑、IgG受體FcRn大型次單元p51調節劑、IL-6受體拮抗劑、整合素α-V/β-3拮抗劑、介白素33配位體抑制劑、類Kelch ECH相關蛋白1調節劑、LDHA基因抑制劑、5-脂肪加氧酶活化蛋白抑制劑、溶血磷脂酸-1受體拮抗劑、質細胞外磷酸醣蛋白調節劑、膜銅胺氧化酶抑制劑、中期因子配位體抑制劑、鹽皮質激素受體拮抗劑、肌凝蛋白2抑制劑、NADPH氧化酶1抑制劑、NADPH氧化酶4抑制劑、NADPH氧化酶抑制劑、NK1受體拮抗劑、核紅血球系2-相關因子2刺激劑、核因子κ B抑制劑、類鴉片受體κ促效劑、類鴉片受體μ拮抗劑、p38 MAP激酶抑制劑、PDE4抑制劑、PDGF受體拮抗劑、PDGF受體β調節劑、磷調因子受體促效劑、PRKAA2基因刺激劑、前蛋白轉化酶PC9抑制劑、前列環素(PGI2)促效劑、蛋白C活化劑、蛋白NOV同系物調節劑、蛋白酪胺酸磷酸酶-1B抑制劑、反應性含氧物種調節劑抑制劑、腎素抑制劑、ρ相關蛋白激酶2抑制劑、SLC22A12抑制劑、鈉葡萄糖轉運體-2抑制劑、溶質載體家族抑制劑、TGFβ配位體抑制劑、TGFβ受體拮抗劑、凝血脂素A2受體拮抗劑、凝血脂素合成抑制劑、組織轉麩醯胺酸酶抑制劑、TRP陽離子通道C5抑制劑、TRP陽離子通道C6抑制劑、色胺酸酶抑制劑、非特異性細胞黏附分子、尿酸鹽陰離子交換劑1抑制劑、升壓素V1a受體拮抗劑、VEGF受體拮抗劑、VIP 1受體促效劑、VIP 2受體促效劑及黃嘌呤氧化酶抑制劑。In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an ACE inhibitor, an adenosine A3 receptor antagonist, an adrenopine stimulator, an albumin regulator, an aldosterone antagonist, an AMP-activated protein kinase stimulator, an vasopressin II AT-2 receptor agonists, vasopressin II receptor antagonists, vasopressin ligand inhibitors, APOA1 gene stimulators, apolipoprotein L1 regulators, bone morphogenetic protein-7 ligand regulators, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor antagonists, CB1 reverse agonists, CCR2 chemokine antagonists, rennet inhibitors, complement C1 subcomponent inhibitors, CX3CR1 chemokine antagonists, cyclooxygenase 1 inhibitors, cyclooxygenase 2 inhibitors, cytochrome P450 11B2 inhibitors, ectonucleotide pyrophosphatase-PDE-2 inhibitors, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, enteropeptidase inhibitors, epoxide hydrolase inhibitors, erythropoietin receptor antagonists, farnesoid X receptor agonists, FGF receptor antagonists, free fatty acid receptor 1 agonists, GHR gene inhibitors, glycoprotein Ib (GPIb) antagonist, GPR40 agonist, GPR84 antagonist, G protein β subunit inhibitor, G protein coupled receptor 120 agonist, G protein coupled receptor 84 modulator, growth hormone ligand, growth hormone receptor agonist, guanylate cyclase receptor agonist, guanylate cyclase stimulator, blood matrix oxygenase 1 regulator, HIF prolinyl hydroxylase inhibitor, IGF1 gene inhibitor, IgG receptor FcRn large subunit p51 regulator, IL-6 receptor antagonist, integrin α-V/β-3 antagonist, interleukin 33 ligand inhibitor, Kelch-like ECH-related protein 1 regulator, LDHA gene inhibitor, 5-lipoxygenase activating protein inhibitor, lysophosphatidic acid-1 receptor antagonist, extracellular phosphoglycoprotein regulator, membrane copper amine oxidase inhibitor, midkine ligand inhibitor, halocorticoid hormone receptor antagonist, myosin 2 inhibitor, NADPH oxidase 1 inhibitor, NADPH oxidase 4 inhibitor, NADPH oxidase inhibitor, NK1 receptor antagonist, nuclear erythroid lineage 2-related factor 2 stimulator, nuclear factor κ B inhibitor, opium receptor κ agonist, opium receptor μ antagonist, p38 MAP kinase inhibitors, PDE4 inhibitors, PDGF receptor antagonists, PDGF receptor β regulators, phospho-regulator receptor agonists, PRKAA2 gene stimulators, proprotein convertase PC9 inhibitors, prostaglandin (PGI2) agonists, protein C activators, protein NOV homolog regulators, protein tyrosine phosphatase-1B inhibitors, reactive oxygen species regulator inhibitors, renin inhibitors, rho-related protein kinase 2 inhibitors, SLC22A12 inhibitors , sodium glucose transporter-2 inhibitors, solute carrier family inhibitors, TGFβ ligand inhibitors, TGFβ receptor antagonists, thrombin A2 receptor antagonists, thrombin synthesis inhibitors, tissue transglutaminase inhibitors, TRP cation channel C5 inhibitors, TRP cation channel C6 inhibitors, tryptophanase inhibitors, non-specific cell adhesion molecules, urate anion exchanger 1 inhibitors, vasopressin V1a receptor antagonists, VEGF receptor antagonists, VIP 1 receptor agonists, VIP 2 receptor agonists and xanthine oxidase inhibitors.
在一些實施例中,本文所提供之方法及組合物包括治療有效量之LPAR1拮抗劑及選自以下之治療有效量之額外治療劑:VEGFR抑制劑、FGFR抑制劑、PDGFR抑制劑、沃他辛(autaxin)抑制劑、GPR84促效劑、PASK抑制劑、CFTR促效劑、JAK1抑制劑、ADAMTS5抑制劑、TOL2/3抑制劑、CTGF抑制劑、可溶性PTX2、抗半乳糖凝集素-3抗體、整合素-αV -β6 /αV -β1 拮抗劑、JNK1抑制劑、鹽皮質激素受體拮抗劑、Nrf2活化劑、凝乳酶抑制劑、PDE抑制劑、NOX1/4抑制劑、白三烯/凝血脂素受體拮抗劑、SLC22A12抑制劑、sGC抑制劑及黃嘌呤氧化酶抑制劑。In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of a VEGFR inhibitor, a FGFR inhibitor, a PDGFR inhibitor, an autaxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2/3 inhibitor, a CTGF inhibitor, a soluble PTX2, an anti-galectin-3 antibody, an integrin-α V -β 6 /α V -β 1 antagonists, JNK1 inhibitors, alkaloid receptor antagonists, Nrf2 activators, chymosin inhibitors, PDE inhibitors, NOX1/4 inhibitors, leukotriene/thrombin receptor antagonists, SLC22A12 inhibitors, sGC inhibitors and xanthine oxidase inhibitors.
在一些實施例中,本文所提供之方法及組合物包括治療有效量之LPAR1拮抗劑及選自以下之治療有效量之額外治療劑:尼達尼布(nintedanib)、吡非尼酮、潘瑞魯單抗(pamrevlumab)、PRM-151、GB-0139、PLN-74809、CC-90001、非瑞酮、BAY1142524、PCS-499、西他那昔布、SER150、RDEA3170、帕利西喹、TMX-049、GLPG1690、GLPG1205、GLPG1972、GLPG4059、GLPG2737、GLPG3970及非戈替尼(filgotinib)。In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of nintedanib, pirfenidone, pamrevlumab, PRM-151, GB-0139, PLN-74809, CC-90001, feretinol, BAY1142524, PCS-499, sitanacoxib, SER150, RDEA3170, pariciquine, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.
在一些實施例中,本文所提供之方法及組合物包括治療有效量之LPAR1拮抗劑及選自以下之治療有效量之額外治療劑:A-717、ACF-TEI、丙胺醯基-麩醯胺酸、ALLN-346、抗SCF248抗體、抗TAGE單株抗體、抗TGF β抗體、AST-120、BAY-2327949、BI-685509、DP-001、DZ-4001、GDT-01、LNP-1892、MEDI-8367、靶向微小RNA之反義寡核苷酸療法、MK-2060、MPC-300-IV、NAV-003、Neo-Kidney Augment™ (NKA)、NP-135、NP-160、NP-251、NRF-803、PBI-4610、PHN-033、R-HSC-010、丹酚酸(salvianolic acid)、SGF-3、SPD-01、Sugaheal變異體、SZ-005、TCF-12、UMC119-06、VAR-400、維瑞瑪(veverimer)、VS-105及XRx-221。 實例 In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti-TAGE monoclonal antibody, anti-TGF β antibody, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, antisense oligonucleotide therapy targeting microRNA, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Augment™ (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, Sugarheal variants , SZ-005, TCF-12, UMC119-06, VAR-400, veverimer, VS-105, and XRx-221.
包括以下實例以展現本發明之具體實施例。熟習此項技術者應瞭解,以下實例中所揭示之技術表示在實踐本發明中良好運行之技術,且因此可視為構成其實踐之特定模式。然而,鑒於本發明,熟習此項技術者應瞭解,此等實例為例示性且非窮盡性的。可在不脫離本發明之精神及範疇的情況下,在所揭示之特定實施例中作出許多變化且仍獲得相似或類似結果。The following examples are included to demonstrate specific embodiments of the present invention. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent techniques that work well in practicing the present invention, and therefore may be considered to constitute specific modes of its practice. However, in view of the present invention, those skilled in the art will appreciate that these examples are illustrative and non-exhaustive. Many changes may be made in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the present invention.
本文所揭示之化合物可以根據以下流程及實例之程序使用適當材料來製備,且藉由以下特定實例來進一步例示。此外,藉由利用本文所描述之程序,結合此項技術中一般的技能,可以易於製備本文中所主張之額外本發明化合物。實例進一步說明製備本發明之化合物的細節。熟習此項技術者將容易地理解,以下製備程序之條件及過程的已知變化可以用於製備此等化合物。為合成作為本發明中所描述之實施例的化合物,待合成之化合物的結構之檢視將提供各取代基之鑑別。在一些情況下,最終產物之一致性可以藉由檢視之過程而使必需起始材料之一致性明顯,給出本文中之實例。化合物可以以其醫藥學上可接受之鹽(諸如上文所描述之彼等)的形式分離。本文所描述之化合物在室溫及室壓下通常為穩定及可分離的。The compounds disclosed herein can be prepared using appropriate materials according to the procedures of the following flows and examples, and are further illustrated by the following specific examples. In addition, by utilizing the procedures described herein, combined with the general skills in this technology, additional compounds of the present invention claimed herein can be easily prepared. The examples further illustrate the details of preparing the compounds of the present invention. Those skilled in the art will readily understand that the conditions of the following preparation procedures and known variations of the processes can be used to prepare these compounds. To synthesize compounds as embodiments described in the present invention, inspection of the structure of the compound to be synthesized will provide identification of each substituent. In some cases, the consistency of the final product can make the consistency of the necessary starting materials apparent by the process of inspection, giving the examples herein. The compound can be isolated in the form of its pharmaceutically acceptable salt (such as those described above). The compounds described herein are generally stable and isolatable at room temperature and pressure.
下文展示製備本文中所揭示之化合物的說明。除非另外規定,否則變數具有與上文所描述相同的含義。下文所呈現之實例意欲說明本發明之具體實施例。在如下文所描述之合成中所採用的適合起始材料、建構嵌段及試劑可購自例如AbovChem、Acros Organics、Astatech、Combi Blocks、Oakwood Chemical或Sigma-Aldrich,或可以常規地藉由文獻中(例如「March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure」, 第5版;John Wiley & Sons或T. Eicher, S. Hauptmann「The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application」, 第2版, Wiley-VCH 2003;Fieser等人「Fiesers´ Reagents for Organic Synthesis」John Wiley & Sons 2000中)所描述之程序來製備。 通用流程 流程 A The following is a description of the preparation of the compounds disclosed herein. Unless otherwise specified, the variables have the same meanings as described above. The examples presented below are intended to illustrate specific embodiments of the present invention. Suitable starting materials, building blocks and reagents used in the syntheses described below are commercially available from, for example, AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical or Sigma-Aldrich, or can be routinely prepared by procedures described in the literature (e.g., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition; John Wiley & Sons or T. Eicher, S. Hauptmann, The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application, 2nd edition, Wiley-VCH 2003; Fieser et al., Fiesers' Reagents for Organic Synthesis, John Wiley & Sons 2000). General Schemes Scheme A
流程 A 提供三唑胺基甲酸酯芳基及雜芳基甲醯胺(VI )之通用合成。在本文所揭示之流程中,「A」可以為鹵素,諸如Cl、Br或I。芳基或雜芳基鹵化物(I)可以容易地藉由相應芳基或雜芳基胺的親電子芳香族鹵化來製備。步驟一中描述芳基及雜芳基胺(I )之醯化。胺(I )可以用醯氯或羧酸利用標準肽偶聯條件處理,諸如使用1-乙基-3-(3-二甲胺基丙基)碳二亞胺(EDC),得到對應醯胺(II )。或者,胺(I )亦可以用氯甲酸酯處理,得到對應胺基甲酸酯(II )。此外,胺(I )可以首先用光氣處理以產生中間物異氰酸酯,其可以隨後由胺捕獲,得到對應脲(II )。 Scheme A provides a general synthesis of triazole aryl and heteroaryl carbamates ( VI ). In the schemes disclosed herein, "A" can be a halogen, such as Cl, Br or I. Aryl or heteroaryl halides (I) can be readily prepared by electrophilic aromatic halogenation of the corresponding aryl or heteroaryl amines. Acylation of aryl and heteroaryl amines ( I ) is described in step 1. Amines ( I ) can be treated with acyl chlorides or carboxylic acids using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amides ( II ). Alternatively, amines ( I ) can also be treated with chloroformates to give the corresponding carbamates ( II ). Alternatively, the amine ( I ) can be first treated with phosgene to produce an intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( II ).
步驟二描述經由交叉偶聯反應之芳基或雜芳基三唑羧酸(IV )之通用合成。芳基或雜芳基鹵化物(II )可以首先經由宮浦硼基化轉化成諸如頻哪醇酸酯之對應酸酯,且隨後與溴三唑羧酸(III )進行鈴木反應條件,得到所需芳基或雜芳基三唑羧酸(IV )。或者,溴三唑羧酸(III )可以首先經由鋰-鹵素交換轉化成有機鋅物質且用氯化鋅捕獲。接下來,根岸(Negishi)與芳基或雜芳基鹵化物(II )交叉偶聯,得到所需芳基或雜芳基三唑羧酸(IV )。Step 2 describes the general synthesis of aryl or heteroaryl triazole carboxylic acids ( IV ) via cross-coupling reactions. The aryl or heteroaryl halide ( II ) can first be converted to a pinacol via Miyura borylation. Ester Correspondence The ester is then subjected to Suzuki reaction conditions with bromotriazole carboxylic acid ( III ) to afford the desired aryl or heteroaryl triazole carboxylic acid ( IV ). Alternatively, bromotriazole carboxylic acid ( III ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Next, Negishi cross coupling with aryl or heteroaryl halide ( II ) affords the desired aryl or heteroaryl triazole carboxylic acid ( IV ).
步驟三描述三唑胺基甲酸酯芳基及雜芳基甲醯胺(VI )之通用合成。芳基或雜芳基三唑羧酸(IV )在用二苯基磷醯基疊氮化物(DPPA)或替代地用1-丙烷膦酸酐(T3P)溶液及疊氮基三甲基矽烷處理時經歷柯提斯重排(Curtius rearrangement)。隨後用醇(V )捕獲中間物異氰酸酯,得到所需芳基或雜芳基三唑胺基甲酸酯(VI )。 流程 B Step three describes the general synthesis of triazole aryl and heteroaryl carbamates ( VI ). The aryl or heteroaryl triazole carboxylic acid ( IV ) undergoes a Curtius rearrangement when treated with diphenylphosphatidyl aziride (DPPA) or alternatively with 1-propanephosphonic anhydride (T3P) solution and trimethylsilane aziride. The intermediate isocyanate is subsequently captured with an alcohol ( V ) to give the desired aryl or heteroaryl triazole carbamate ( VI ). Scheme B
流程B提供三唑胺基甲酸酯芳基及雜芳基甲醯胺(VI)之替代合成。步驟一描述經由交叉偶聯反應進行胺基芳基或雜芳基三唑胺基甲酸酯(XI )之通用合成。溴三唑胺基甲酸酯(X )可以首先經由鋰-鹵素交換轉化成有機鋅物質且用氯化鋅捕獲。接下來,根岸與芳基或雜芳基鹵化物(I )交叉偶聯,得到所需胺基芳基或雜芳基三唑胺基甲酸酯(XI )。或者,芳基或雜芳基鹵化物(I)可以首先經由宮浦硼基化轉化成諸如頻哪醇酸酯之對應酸酯,且隨後與溴三唑胺基甲酸酯(X )進行鈴木反應條件,得到所需胺基芳基或雜芳基三唑胺基甲酸酯(XI )。Scheme B provides an alternative synthesis of triazole aryl and heteroaryl carbamates (VI). Step 1 describes the general synthesis of aminoaryl or heteroaryl triazole carbamates ( XI ) via a cross-coupling reaction. The bromotriazole carbamate ( X ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Next, cross-coupling with an aryl or heteroaryl halide ( I ) affords the desired aminoaryl or heteroaryl triazole carbamate ( XI ). Alternatively, the aryl or heteroaryl halide (I) can first be converted to a pinacol such as via Miyaura borylation. Ester Correspondence The ester is then reacted with bromotriazole carbamate ( X ) under Suzuki reaction conditions to obtain the desired aminoaryl or heteroaryl triazole carbamate ( XI ).
步驟 1A-B 描述 胺基芳基或雜芳基三唑胺基甲酸酯(XI)之替代合成 。胺基甲酸三級丁酯(XII )可以容易地藉由用二-二碳酸三級丁酯處理對應芳基或雜芳基胺來製備。芳基或雜芳基鹵化物(XII )可以首先經由宮浦硼基化轉化成諸如頻哪醇酸酯之對應酸酯,且隨後與溴三唑胺基甲酸酯(X )進行鈴木反應條件,得到所需胺基芳基或雜芳基三唑胺基甲酸酯(XIII )。或者,溴三唑胺基甲酸酯(X )可以首先經由鋰-鹵素交換轉化成有機鋅物質且用氯化鋅捕獲。隨後,根岸與芳基或雜芳基鹵化物交叉偶聯(XII ),得到所需芳基或雜芳基三唑胺基甲酸酯(XIII )。接下來,可以用諸如鹽酸(HCl)之酸處理三級丁基芳基或雜芳基三唑胺基甲酸酯(XIII ),得到呈鹽酸鹽形式之胺基芳基或雜芳基三唑胺基甲酸酯(XI )。 Step 1A-B Description Alternative synthesis of aminoaryl or heteroaryl triazole carbamates (XI). Tributyl carbamates ( XII ) can be readily prepared by treating the corresponding aryl or heteroaryl amine with tributyl dicarbonate. The aryl or heteroaryl halide ( XII ) can first be converted to a pinacol via Miyura borylation. Ester Correspondence esters and subsequently subjected to Suzuki reaction conditions with bromotriazole carbamate ( X ) to afford the desired aminoaryl or heteroaryl triazole carbamate ( XIII ). Alternatively, the bromotriazole carbamate ( X ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Subsequently, Negishi cross-coupling with an aryl or heteroaryl halide ( XII ) affords the desired aryl or heteroaryl triazole carbamate ( XIII ). Next, the tertiary butyl aryl or heteroaryl triazole carbamate ( XIII ) can be treated with an acid such as hydrochloric acid (HCl) to afford the aminoaryl or heteroaryl triazole carbamate ( XI ) in the form of a hydrochloride salt.
步驟二描述三唑胺基甲酸酯芳基及雜芳基甲醯胺(VI )之通用合成。胺基芳基或雜芳基三唑胺基甲酸酯(XI )可以用醯氯或羧酸利用標準肽偶聯條件處理,諸如使用1-乙基-3-(3-二甲胺基丙基)碳二亞胺(EDC),得到對應醯胺(VI )。或者,胺(XI )亦可以用氯甲酸酯處理,得到對應胺基甲酸酯(VI )。此外,胺(XI )可以首先用光氣處理以產生中間物異氰酸酯,其可以隨後由胺捕獲,得到對應脲(VI )。 流程 C 。Step 2 describes the general synthesis of triazole aryl and heteroaryl carbamates ( VI ). Aminaryl or heteroaryl triazole carbamates ( XI ) can be treated with acyl chlorides or carboxylic acids using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amides ( VI ). Alternatively, amines ( XI ) can also be treated with chloroformates to give the corresponding carbamates ( VI ). In addition, amines ( XI ) can first be treated with phosgene to produce the intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( VI ). Scheme C .
流程 C 提供芳基或雜芳基三唑胺基甲酸酯(VI )之通用替代合成。步驟一描述經由交叉偶聯反應之芳基或雜芳基三唑羧酸(XIV )之通用合成。芳基或雜芳基鹵化物(XII )可以首先經由宮浦硼基化轉化成諸如頻哪醇酸酯之對應酸酯,且隨後與溴三唑羧酸(III )進行鈴木反應條件,得到所需芳基或雜芳基三唑羧酸(XIV )。或者,溴三唑羧酸(III )可以首先經由鋰-鹵素交換轉化成有機鋅物質且用氯化鋅捕獲。接下來,根岸(Negishi)與芳基或雜芳基鹵化物(XII )交叉偶聯,得到所需芳基或雜芳基三唑羧酸(XIV )。 Scheme C provides a general alternative synthesis of aryl or heteroaryl triazole carbamates ( VI ). Step 1 describes the general synthesis of aryl or heteroaryl triazole carboxylic acids ( XIV ) via a cross-coupling reaction. The aryl or heteroaryl halide ( XII ) can first be converted to a pinacol via Miyura borylation. Ester Correspondence The ester is then subjected to Suzuki reaction conditions with bromotriazole carboxylic acid ( III ) to afford the desired aryl or heteroaryl triazole carboxylic acid ( XIV ). Alternatively, bromotriazole carboxylic acid ( III ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Next, Negishi cross coupling with aryl or heteroaryl halide ( XII ) affords the desired aryl or heteroaryl triazole carboxylic acid ( XIV ).
步驟二描述含有胺基甲酸酯之芳基或雜芳基三唑之通用合成(XIII )。芳基或雜芳基三唑羧酸(XIV )在用二苯基磷醯基疊氮化物(DPPA)或替代地用1-丙烷膦酸酐(T3P)溶液及疊氮基三甲基矽烷處理時經歷柯提斯重排。隨後用醇(V )捕獲中間物異氰酸酯,得到所需芳基或雜芳基三唑胺基甲酸酯(XIII )。步驟三描述胺基芳基或雜芳基三唑胺基甲酸酯(XI )之通用合成。可以用諸如鹽酸(HCl)之酸處理三級丁基芳基或雜芳基胺基甲酸酯(XIII ),得到呈鹽酸鹽形式之胺基芳基或雜芳基三唑胺基甲酸酯(XI )。Step two describes the general synthesis of aryl or heteroaryl triazoles containing carbamates ( XIII ). Aryl or heteroaryl triazole carboxylic acids ( XIV ) undergo Curtis rearrangement when treated with diphenylphosphatidyl aziride (DPPA) or alternatively with 1-propanephosphonic anhydride (T3P) solution and trimethylsilane aziride. Subsequent capture of the intermediate isocyanate with an alcohol ( V ) affords the desired aryl or heteroaryl triazole carbamate ( XIII ). Step three describes the general synthesis of aminoaryl or heteroaryl triazole carbamates ( XI ). The tertiary butyl aryl or heteroaryl carbamate ( XIII ) can be treated with an acid such as hydrochloric acid (HCl) to afford the aminoaryl or heteroaryl triazole carbamate ( XI ) in the form of a hydrochloride salt.
步驟四描述三唑胺基甲酸酯芳基及雜芳基甲醯胺(VI )之通用合成。胺基芳基或雜芳基三唑胺基甲酸酯(XI )可以用醯氯或羧酸利用標準肽偶聯條件處理,諸如使用1-乙基-3-(3-二甲胺基丙基)碳二亞胺(EDC),得到對應醯胺(VI )。或者,胺(XI )亦可以用氯甲酸酯處理,得到對應胺基甲酸酯(VI )。在使用氯甲酸苯酯之情況下,可以用胺處理所得胺基甲酸苯酯(VI )以產生對應脲(VI )。此外,胺(XI )可以首先用光氣處理以產生中間物異氰酸酯,其可以隨後由胺捕獲,得到對應脲(VI )。 流程 D Step 4 describes the general synthesis of triazole aryl and heteroaryl carbamates ( VI ). Aminaryl or heteroaryl triazole carbamates ( XI ) can be treated with acyl chlorides or carboxylic acids using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amides ( VI ). Alternatively, amines ( XI ) can also be treated with chloroformates to give the corresponding carbamates ( VI ). In the case of using phenyl chloroformate, the resulting phenyl carbamate ( VI ) can be treated with an amine to produce the corresponding urea ( VI ). In addition, amines ( XI ) can first be treated with phosgene to produce the intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( VI ). Scheme D
流程 D 描述三唑胺基甲酸酯芳基及雜芳基甲醯胺(VI )之合成的替代合成。E可以為鹵素,諸如-Br或-I。在步驟一中,芳基或雜芳基二鹵化物(XV )與炔丙基醇進行薗頭偶聯以產生芳基或雜芳基-炔(XVI )。隨後炔與疊氮化合物進行熱或催化環加成以在步驟二中產生對應羥甲基三唑(XVII)。最後,在步驟三中,使用四甲基哌啶基氧基(TEMPO)與亞氯酸鈉使一級醇氧化,得到三唑羧酸(XVIII )。 Scheme D describes an alternative synthesis of triazole carbamate aryl and heteroaryl carboxamides ( VI ). E can be a halogen, such as -Br or -I. In step one, the aryl or heteroaryl dihalide ( XV ) undergoes a sonogaoka coupling with a propargyl alcohol to produce an aryl or heteroaryl-alkyne ( XVI ). The alkyne is then subjected to a thermal or catalytic cycloaddition with an azido compound to produce the corresponding hydroxymethyltriazole (XVII) in step two. Finally, in step three, the primary alcohol is oxidized using tetramethylpiperidinyloxy (TEMPO) and sodium chlorite to give the triazole carboxylic acid ( XVIII ).
在步驟四中,三唑羧酸(XVIII )諸如藉由用亞硫醯氯處理而以甲酯(XIX )形式受保護。在步驟五中,芳基或雜芳基鹵化物(XIX )隨後與胺基甲酸三級丁酯進行巴哈法型胺化(Buchwald -type amination)以產生經Boc保護之胺(XX )。In step 4, the triazole carboxylic acid ( XVIII ) is protected as the methyl ester ( XIX ) by treatment with thionyl chloride. In step 5, the aryl or heteroaryl halide ( XIX ) is then subjected to a Buchwald-type amination with tert-butyl carbamate to produce the Boc-protected amine ( XX ).
在步驟六中,經Boc保護之胺(XX )曝露於鹽酸揭露鹽酸鹽(XXI ),其可以在步驟七中用醯氯或羧酸利用標準肽偶聯條件反應,諸如使用1-乙基-3-(3-二甲胺基丙基)碳二亞胺(EDC),得到對應醯胺(XXII )。或者,胺(XXI )亦可以用氯甲酸酯處理,得到對應胺基甲酸酯(XXII )。此外,胺(XXI )可以首先用光氣處理以產生中間物異氰酸酯,其可以隨後由胺捕獲,得到對應脲(XXII )。在步驟八中,三唑酯(XXII )可以在用諸如氫氧化鈉之鹼處理時水解,展現三唑羧酸(IV )。最後,步驟九描述三唑羧酸(IV )經由用二苯基磷醯基疊氮化物(DPPA)或者用1-丙烷膦酸酐(T3P)溶液及疊氮基三甲基矽烷處理之柯提斯重排。隨後用醇(V )捕獲中間物異氰酸酯,得到所需芳基-或雜芳基-三唑胺基甲酸酯(VI )。 實例 1 :製備 4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 ( 中間物 1) 步驟 1 : 4,5- 二溴 -2H-1,2,3- 三唑 In step six, the Boc-protected amine ( XX ) is exposed to hydrochloric acid to reveal the hydrochloride ( XXI ), which can be reacted in step seven with an acyl chloride or carboxylic acid using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amide ( XXII ). Alternatively, the amine ( XXI ) can also be treated with a chloroformate to give the corresponding carbamate ( XXII ). In addition, the amine ( XXI ) can first be treated with phosgene to produce an intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( XXII ). In step eight, the triazole ester ( XXII ) can be hydrolyzed upon treatment with a base such as sodium hydroxide to reveal the triazole carboxylic acid ( IV ). Finally, step nine describes the Curtis rearrangement of the triazole carboxylic acid ( IV ) via treatment with diphenylphosphatidyl azide (DPPA) or with 1-propanephosphonic anhydride (T3P) solution and trimethylsilane azide. The intermediate isocyanate is then captured with an alcohol ( V ) to give the desired aryl- or heteroaryl-triazole carbamate ( VI ). Example 1 : Preparation of 4- bromo -1- methyl -1H-1,2,3 - triazole -5- carboxylic acid ( Intermediate 1) Step 1 : 4,5- dibromo -2H-1,2,3 -triazole
在40℃下將溴(2.8 mol)添加至2H-1,2,3-三唑(1.4 mol)於水(600 mL)中之溶液中。在40℃下攪拌所得混合物2小時。冷卻至室溫後,藉由過濾收集沈澱物。將固體用水(2 × 300 mL)洗滌且在真空下乾燥以得到4,5-二溴-2H-1,2,3-三唑。 步驟 2 : 4,5- 二溴 -1- 甲基 -1H-1,2,3- 三唑 Bromine (2.8 mol) was added to a solution of 2H-1,2,3-triazole (1.4 mol) in water (600 mL) at 40°C. The resulting mixture was stirred at 40°C for 2 hours. After cooling to room temperature, the precipitate was collected by filtration. The solid was washed with water (2 × 300 mL) and dried under vacuum to give 4,5-dibromo-2H-1,2,3-triazole. Step 2 : 4,5- Dibromo -1- methyl -1H-1,2,3- triazole
向4,5-二溴-2H-1,2,3-三唑(704 mmol)及K2 CO3 (1.4 mol)於THF (1000 mL)中之混合物中添加碘甲烷(1.0 mol)。在室溫下攪拌混合物12小時。過濾混合物且用乙酸乙酯(2 × 500 mL)洗滌濾餅,將濾液在40℃下濃縮以得到粗產物,該粗產物藉由管柱層析純化以得到4,5-二溴-1-甲基-1H-1,2,3-三唑。步驟 3 : 4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 甲醛 To a mixture of 4,5-dibromo-2H-1,2,3-triazole (704 mmol) and K 2 CO 3 (1.4 mol) in THF (1000 mL) was added iodomethane (1.0 mol). The mixture was stirred at room temperature for 12 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (2×500 mL), the filtrate was concentrated at 40°C to give a crude product, which was purified by column chromatography to give 4,5-dibromo-1-methyl-1H-1,2,3-triazole. Step 3 : 4 - Bromo - 1- methyl -1H-1,2,3- triazole -5- carbaldehyde
在-10℃下向4,5-二溴-1-甲基-1H-1,2,3-三唑(168.0 mmol)於THF (600 mL)中之溶液中添加異丙基氯化鎂(252.0 mmol)。將混合物攪拌15 min,添加DMF (840 mmol)。在1小時之後,用250 mL飽和氯化銨處理混合物且用DCM (2×350 mL)萃取。將合併之有機物用250 mL鹽水洗滌,經Na2 SO4 乾燥,過濾且濃縮以得到4-溴-1-甲基-1H-1,2,3-三唑-5-甲醛。 步驟 4 : 4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 To a solution of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (168.0 mmol) in THF (600 mL) at -10 °C was added isopropylmagnesium chloride (252.0 mmol). The mixture was stirred for 15 min and DMF (840 mmol) was added. After 1 h, the mixture was treated with 250 mL of saturated ammonium chloride and extracted with DCM (2 x 350 mL). The combined organics were washed with 250 mL of brine, dried over Na2SO4 , filtered and concentrated to give 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde. Step 4 : 4- Bromo -1- methyl -1H-1,2,3- triazole -5- carboxylic acid
將過硫酸氫鉀(651 mmol)添加至4-溴-1-甲基-1H-1,2,3-三唑-5-甲醛(536 mmol)於DMF (800 mL)中之溶液中且將所得懸浮液在室溫下攪拌隔夜。將混合物反應物用H2 O (1000 mL)稀釋,用1N HCl調節至pH 3,且將水相用乙酸乙酯(3 × 800 mL)萃取。將合併之有機物用飽和Na2 CO3 (2 × 500 mL)洗滌,將水相用1N HCl調節至pH 3。將沈澱物藉由過濾分離且在減壓下乾燥以得到4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物1)。 實例 2 :製備 (R)-(4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯苯基 ) 乙酯 ( 中間物 2A) Potassium hydrogen persulfate (651 mmol) was added to a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (536 mmol) in DMF (800 mL) and the resulting suspension was stirred at room temperature overnight. The mixture reaction was diluted with H 2 O (1000 mL), adjusted to pH 3 with 1N HCl, and the aqueous phase was extracted with ethyl acetate (3×800 mL). The combined organics were washed with saturated Na 2 CO 3 (2×500 mL), and the aqueous phase was adjusted to pH 3 with 1N HCl. The precipitate was separated by filtration and dried under reduced pressure to give 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1). Example 2 : Preparation of (R)-(4- bromo -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Intermediate 2A)
向4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(24.3 mmol)於甲苯(80 mL)中之懸浮液中添加DPPA (24.5 mmol)、三乙胺(24.5 mmol)及(R)-1-(2-氯苯基)乙-1-醇(36.5 mmol)。在80℃下加熱混合物3小時。過濾反應混合物,且在真空中濃縮濾液。藉由二氧化矽層析純化殘餘物,得到(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(中間物2A)。 實例 3 :製備 (R)-(4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 中間物 2B) To a suspension of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (24.3 mmol) in toluene (80 mL) were added DPPA (24.5 mmol), triethylamine (24.5 mmol) and (R)-1-(2-chlorophenyl)ethan-1-ol (36.5 mmol). The mixture was heated at 80 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography to give (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A). Example 3 : Preparation of (R)-(4- bromo -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Intermediate 2B)
在氬氣氛圍下,將DMF中之4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(95 mmol)、50% 1-丙烷膦酸酐溶液(143 mmol)及疊氮基三甲基矽烷(143 mmol)懸浮於THF (350 mL)中。添加三乙胺(143 mmol)且使所得溶液攪拌30分鐘。添加(R)-1-(2-氯吡啶-3-基)乙-1-醇(143 mmol)且在回流下加熱混合物,其中連接有二級起泡器以允許通氣持續12小時。將反應混合物冷卻至室溫,且在真空中移除THF。將所得粗物質溶解於500 mL乙酸乙酯中且用300 mL水萃取三次。粗混合物隨後經硫酸鈉乾燥,過濾且濃縮濾液。粗物質藉由矽膠管柱層析純化,得到(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物2B)。 實例 4 :製備 (R)-(4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟吡啶 -3- 基 ) 乙酯 ( 中間物 2C) 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (95 mmol), 50% 1-propanephosphonic anhydride solution (143 mmol) and trimethylsilane (143 mmol) in DMF were suspended in THF (350 mL) under an argon atmosphere. Triethylamine (143 mmol) was added and the resulting solution was stirred for 30 minutes. (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (143 mmol) was added and the mixture was heated at reflux with a secondary bubbler attached to allow aeration for 12 hours. The reaction mixture was cooled to room temperature and the THF was removed in vacuo. The resulting crude material was dissolved in 500 mL of ethyl acetate and extracted three times with 300 mL of water. The crude mixture was then dried over sodium sulfate, filtered and the filtrate was concentrated. The crude material was purified by silica gel column chromatography to give (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Intermediate 2B). Example 4 : Preparation of (R)-(4- bromo -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Intermediate 2C)
遵循描述於實例3中之合成(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物2B)的步驟,使用(R)-1-(2-氟吡啶-3-基)乙-1-醇(143 mmol)代替(R)-1-(2-氯吡啶-3-基)乙-1-醇,得到(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟吡啶-3-基)乙酯(中間物2C)。 實例5:製備(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(3-氟苯基)乙酯(中間物2D) Following the procedure described in Example 3 for the synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B), using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (143 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (R)-1-(2-fluoropyridin-3-yl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C) was obtained. Example 5: Preparation of 1-(3-fluorophenyl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2D)
遵循描述於實例3中之合成(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物2B)的步驟,使用(R)-1-(3-氟苯基)乙-1-醇(230 mmol)代替(R)-1-(2-氯吡啶-3-基)乙-1-醇,得到(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(3-氟苯基)乙酯(中間物2D)。 實例 6 : 製備 4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸甲酯 ( 中間物 3A) Following the procedure described in Example 3 for the synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B), using (R)-1-(3-fluorophenyl)ethan-1-ol (230 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (R)-1-(3-fluorophenyl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2D) was obtained. Example 6 : Preparation of methyl 4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylate ( Intermediate 3A)
中間物3A一般根據流程D製備。 步驟 1 : 3-(5- 溴吡啶 -2- 基 ) 丙 -2- 炔 -1- 醇 Intermediate 3A is generally prepared according to Scheme D. Step 1 : 3-(5- bromopyridin -2- yl ) prop -2- yn -1- ol
在氮氣氛圍下向5-溴-2-碘吡啶(352.2 mmol)於THF (400 mL)中之混合物中添加化合物丙-2-炔-1-醇(370 mmol)、三乙胺(1.06 mol)、碘化亞銅(17.6 mmol)及雙(三苯膦)氯化鈀(II) (10.6 mmol)。在室溫下攪拌反應混合物16小時。反應完成後,將混合物用水(500 ml)稀釋且將固體過濾。將濾液用乙酸乙酯(3 × 500 ml)萃取。有機層經無水硫酸鈉乾燥且在減壓下濃縮。將殘餘物用乙酸乙酯及乙醚濕磨且攪拌2小時並過濾。將濾餅用乙醚洗滌以得到3-(5-溴吡啶-2-基)丙-2-炔-1-醇。 步驟 2 : (4-(5- 溴吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 甲醇 To a mixture of 5-bromo-2-iodopyridine (352.2 mmol) in THF (400 mL) were added compound prop-2-yn-1-ol (370 mmol), triethylamine (1.06 mol), cuprous iodide (17.6 mmol) and bis(triphenylphosphine)palladium(II) chloride (10.6 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was diluted with water (500 ml) and the solid was filtered. The filtrate was extracted with ethyl acetate (3 × 500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether and stirred for 2 hours and filtered. The filter cake was washed with ether to give 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol. Step 2 : (4-(5- bromopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) methanol
將碘化亞銅(0.94 mmol)及碘化四丁銨(0.94 mmol)混合在一起且溶解於THF (30 mL)中,攪拌20分鐘以得到溶液。隨後,添加3-(5-溴-2-吡啶基)丙-2-炔-1-醇(9.43 mmol)且將反應物用氬氣鼓泡2分鐘。添加五甲基環戊二烯基雙(三苯膦)氯化釕(II) (0.47 mmol)及疊氮基甲基三甲基矽烷(24 mmol)且將反應物密封並加熱至80℃持續16小時。將反應混合物在真空中濃縮,且隨後再溶解於THF (50 mL)中。在室溫下逐滴添加氟化四丁銨(10 mL之1 M溶液於THF中)且攪拌1小時。將混合物用飽和碳酸氫鈉溶液(100 mL)淬滅且用DCM (3 × 100 mL)萃取。有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由矽膠層析純化以得到(4-(5-溴吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)甲醇。步驟 3 : 4-(5- 溴吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 Cuprous iodide (0.94 mmol) and tetrabutylammonium iodide (0.94 mmol) were mixed together and dissolved in THF (30 mL), stirred for 20 minutes to give a solution. Then, 3-(5-bromo-2-pyridyl)prop-2-yn-1-ol (9.43 mmol) was added and the reaction was bubbled with hydrogen for 2 minutes. Pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (0.47 mmol) and azidomethyltrimethylsilane (24 mmol) were added and the reaction was sealed and heated to 80°C for 16 hours. The reaction mixture was concentrated in vacuo and then redissolved in THF (50 mL). Tetrabutylammonium fluoride (10 mL of 1 M solution in THF) was added dropwise at room temperature and stirred for 1 hour. The mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with DCM (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol. Step 3 : 4-(5- bromopyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid
將[5-(5-溴-2-吡啶基)-3-甲基-三唑-4-基]甲醇(4.83 mmol)、2,2,6,6-四甲基哌啶基氧基(TEMPO) (0.48 mmol)及磷酸二氫鈉(12.08 mmol)懸浮於乙腈(50 ml)及水(40 ml)中。將溶液加熱至45℃。隨後,在1小時內同時添加10 ml之1 M亞氯酸鈉水溶液及單獨的次氯酸鈉溶液(10 ml之0.01 M水溶液)。在45℃下攪拌反應物16小時。將混合物冷卻至室溫且濃縮以移除乙腈。過濾產物且用水(2×50 mL)及乙醚(50 mL)洗滌濾餅,得到4-(5-溴吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸。LCMS M/Z (M+1)=283.1。 步驟 4 : 4-(5- 溴吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸甲酯 [5-(5-Bromo-2-pyridinyl)-3-methyl-triazol-4-yl]methanol (4.83 mmol), 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) (0.48 mmol) and sodium dihydrogen phosphate (12.08 mmol) were suspended in acetonitrile (50 ml) and water (40 ml). The solution was heated to 45°C. Subsequently, 10 ml of a 1 M aqueous sodium chlorite solution and a separate sodium hypochlorite solution (10 ml of a 0.01 M aqueous solution) were added simultaneously over 1 hour. The reaction was stirred at 45°C for 16 hours. The mixture was cooled to room temperature and concentrated to remove the acetonitrile. The product was filtered and the filter cake was washed with water (2×50 mL) and ether (50 mL) to give 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. LCMS M/Z (M+1)=283.1. Step 4 : 4-(5- bromopyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester
將4-(5-溴吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(14.1 mmol)溶解於40 ml之甲醇中。用冰浴使溶液冷卻至0℃。在15 min內逐滴添加三甲基矽烷基重氮甲烷(18.4 mmol)。移除冰浴且將反應物攪拌5小時。藉由添加飽和碳酸氫鈉水溶液將反應物淬滅且用乙酸乙酯萃取。有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由矽膠層析純化以得到4-(5-溴吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯。 步驟 5 : 4-(5-(( 三級丁氧基羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸甲酯 4-(5-Bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (14.1 mmol) was dissolved in 40 ml of methanol. The solution was cooled to 0°C with an ice bath. Trimethylsilyldiazomethane (18.4 mmol) was added dropwise over 15 min. The ice bath was removed and the reaction was stirred for 5 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate. Step 5 : 4-(5-(( tert-butyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester
將4-(5-溴吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯(11.1 mmol)、胺基甲酸三級丁酯(33 mmol)、碳酸銫(33 mmol)及Xantphos Pd G3預催化劑(1.1 mmol)懸浮於二㗁烷(50 ml)中。用氬氣對懸浮液進行鼓泡持續10分鐘,且隨後加熱至95℃持續4小時。反應完成後,將混合物冷卻且用水(100 ml)稀釋並用乙酸乙酯(2 × 100 ml)萃取。有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由矽膠層析純化以得到4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯。 步驟 6 : 4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸甲酯鹽酸鹽 ( 中間物 3A) Methyl 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (11.1 mmol), tributyl carbamate (33 mmol), cesium carbonate (33 mmol) and Xantphos Pd G3 precatalyst (1.1 mmol) were suspended in dioxane (50 ml). The suspension was bubbled with argon for 10 minutes and then heated to 95°C for 4 hours. After the reaction was completed, the mixture was cooled and diluted with water (100 ml) and extracted with ethyl acetate (2 × 100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester. Step 6 : 4-(5- aminopyridin -2 - yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester hydrochloride ( Intermediate 3A)
向4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯(6 mmol)中添加含4 M HCl之二㗁烷(14 mL)且將反應物在室溫下劇烈攪拌3小時。反應完成後,將溶液在真空中濃縮以得到4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯鹽酸鹽(中間物3A)。 實例 7 : 製備 4-(5-(( 三級丁氧基羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 ( 中間物 3B) To methyl 4-(5-((tert-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (6 mmol) was added 4 M HCl in dioxane (14 mL) and the reaction was vigorously stirred at room temperature for 3 hours. After the reaction was complete, the solution was concentrated in vacuo to give methyl 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate hydrochloride (Intermediate 3A). Example 7 : Preparation of 4-(5-(( tert-butyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3 -triazole -5- carboxylic acid ( Intermediate 3B)
將4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(50 mmol)溶解於500 mL四氫呋喃中且浸沒於-78℃浴中持續15分鐘。在15分鐘內逐滴添加雙(三甲基矽基)胺基鋰於四氫呋喃(54 mmol)中之1 M溶液。在20分鐘內逐滴添加正丁基鋰(105 mmol)於己烷中之2.5 M溶液且將其攪拌額外1小時。在15分鐘內逐滴添加氯化鋅(105 mmol)於2-甲基四氫呋喃中之1.9 M溶液。藉由浸沒於水浴中使反應混合物升溫至環境溫度且將其攪拌30分鐘。將所得混合物用氬氣鼓泡10 min,且隨後添加(6-溴吡啶-3-基)胺基甲酸三級丁酯(50 mmol)及與二氯甲烷複合之[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) (5 mmol)。將反應物在75℃下加熱3小時,且隨後冷卻至環境溫度。將反應物用350 mL之2 M氫氧化鈉水溶液及300 mL二乙醚稀釋。分離水層,且將有機層用1 M氫氧化鈉水溶液(100 mL)萃取。將合併之水層用乙酸乙酯及二乙醚之1:1混合物(150 mL × 2)洗滌。在10 min內在劇烈攪拌下逐滴添加80 mL濃鹽酸以將pH調節至4。將混合物過濾,且將濾餅用水(100 mL)及乙酸乙酯與二乙醚之1:1混合物(100 mL × 2)洗滌。將沈澱物在減壓下乾燥以得到4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物3B)。 實例 8 : 製備 (R)-(1- 甲基 -4-(4-(2,2,2- 三氟乙醯胺基 ) 苯基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(3- 氟苯基 ) 乙 酯 ( 化合物 1) 步驟 1 : (R)-(4-(4- 胺基苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(3- 氟苯基 ) 乙 酯 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (50 mmol) was dissolved in 500 mL tetrahydrofuran and immersed in a -78 °C bath for 15 minutes. A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (54 mmol) was added dropwise over 15 minutes. A 2.5 M solution of n-butyllithium (105 mmol) in hexanes was added dropwise over 20 minutes and stirred for an additional hour. A 1.9 M solution of zinc chloride (105 mmol) in 2-methyltetrahydrofuran was added dropwise over 15 minutes. The reaction mixture was allowed to warm to ambient temperature by immersion in a water bath and stirred for 30 minutes. The resulting mixture was bubbled with argon for 10 min, and then tributyl (6-bromopyridin-3-yl)carbamate (50 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mmol) complexed with dichloromethane were added. The reaction was heated at 75 °C for 3 hours, and then cooled to ambient temperature. The reaction was diluted with 350 mL of 2 M aqueous sodium hydroxide solution and 300 mL of diethyl ether. The aqueous layer was separated, and the organic layer was extracted with 1 M aqueous sodium hydroxide solution (100 mL). The combined aqueous layers were washed with a 1:1 mixture of ethyl acetate and diethyl ether (150 mL × 2). 80 mL of concentrated hydrochloric acid was added dropwise under vigorous stirring within 10 min to adjust the pH to 4. The mixture was filtered, and the filter cake was washed with water (100 mL) and a 1:1 mixture of ethyl acetate and diethyl ether (100 mL × 2). The precipitate was dried under reduced pressure to give 4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 3B). Example 8 : Preparation of (R)-1- (3- fluorophenyl )ethyl(1- methyl -4-(4-(2,2,2- trifluoroacetamido ) phenyl )-1H-1,2,3- triazol - 5- yl ) carbamate ( Compound 1 ) Step 1 : (R)-(4-(4- aminophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(3- fluorophenyl ) ethyl ester
藉由氬氣將(R )-(4-溴-1-甲基-1H -1,2,3-三唑-5-基)胺基甲酸1-(3-氟苯基)乙酯(中間物2D)(0.370 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯胺(0.407 mmol)、四(三苯基膦)鈀(0)(0.037 mmol)及碳酸鈉(1.11 mmol)於1,4-二㗁烷/水(3:1,3.0 mL)中之混合物脫氣10分鐘。密封容器且在100℃下加熱18小時。將反應物冷卻至室溫,用NH4 Cl飽和水溶液稀釋,且用二氯甲烷萃取。合併之有機層用鹽水洗滌,經MgSO4 乾燥,過濾且在減壓下濃縮。粗材料藉由矽膠層析純化,得到(R)-(4-(4-胺基苯基)-1-甲基-1H -1,2,3-三唑-5-基)胺基甲酸1-(3-氟苯基)乙酯(中間物8C)。 步驟 2 : (R)-(1- 甲基 -4-(4-(2, 2, 2- 三氟乙醯胺基 ) 苯基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(3- 氟苯基 ) 乙 酯 ( 化合物 1) A mixture of ( R )-1-(3-fluorophenyl)ethyl(4-bromo-1-methyl- 1H -1,2,3-triazol-5-yl)carbamate (Intermediate 2D) (0.370 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)aniline (0.407 mmol), tetrakis(triphenylphosphine)palladium(0) (0.037 mmol) and sodium carbonate (1.11 mmol) in 1,4-dioxane/water (3:1, 3.0 mL) was degassed by hydrogen for 10 min. The vessel was sealed and heated at 100 °C for 18 h. The reaction was cooled to room temperature, diluted with saturated aqueous NH4Cl solution, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give (R)-(4-(4-aminophenyl)-1-methyl- 1H -1,2,3-triazol-5-yl)carbamic acid 1-(3-fluorophenyl)ethyl ester (Intermediate 8C). Step 2 : (R)-(1- methyl -4-(4-(2, 2, 2- trifluoroacetamido ) phenyl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(3- fluorophenyl ) ethyl ester ( Compound 1)
向(R )-(4-(4-胺基苯基)-1-甲基-1H -1,2,3-三唑-5-基)胺基甲酸1-(3-氟苯基)乙酯(中間物8C)(0.082 mmol)於二氯甲烷(2.0 mL)中之溶液中添加三氟乙酸酐(0.122 mmol)。將溶液在室溫下攪拌3小時。在減壓下濃縮反應物且藉由逆相層析純化,得到(R)-(1-甲基-4-(4-(2,2,2-三氟乙醯胺基)苯基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(3-氟苯基)乙酯(化合物6)。(MS(m/z ) 452.0[M H]+ )。1H NMR (400 MHz, DMSO-d6,旋轉異構體之混合物) δ 11.36 (s, 1H)、9.97(主要)及9.55(次要)(s, 1H)、7.73(s, 4H)、7.53-6.66(m, 4H)、5.89-5.60 (m, 1H)、3.85 (s, 3H)、1.56(主要)及1.24(次要)(s, 3H)。 實例 9 : 製備 [(1R)-1-(2- 氯 -3- 吡啶基 ) 乙基 ] N-[5-[5-[(1- 氰基環丙烷羰基 ) 胺基 ] 嘧啶基 -2- 基 ]-3- 甲基 - 三唑 -4- 基 ] 胺基甲酸酯 ( 化合物 2) 步驟 1 : [(1R)-1-(2- 氯 -3- 吡啶基 ) 乙基 ] N-[5-(5- 胺基嘧啶 -2- 基 )-3- 甲基 - 三唑 -4- 基 ] 胺基甲酸酯 To a solution of ( R )-1-(3-fluorophenyl)ethyl(4-(4-aminophenyl)-1-methyl- 1H -1,2,3-triazol-5-yl)carbamate (Intermediate 8C) (0.082 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic anhydride (0.122 mmol). The solution was stirred at room temperature for 3 hours. The reactant was concentrated under reduced pressure and purified by reverse phase chromatography to give (R)-1-(3-fluorophenyl)ethyl(1-methyl-4-(4-(2,2,2-trifluoroacetamido)phenyl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 6). (MS ( m/z ) 452.0 [MH] + ). 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 11.36 (s, 1H), 9.97 (major) and 9.55 (minor) (s, 1H), 7.73 (s, 4H), 7.53-6.66 (m, 4H), 5.89-5.60 (m, 1H), 3.85 (s, 3H), 1.56 (major) and 1.24 (minor) (s, 3H). Example 9 : Preparation of [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-[5-[(1- cyanocyclopropanecarbonyl ) amino ] pyrimidinyl -2- yl ]-3- methyl - triazol -4- yl ] carbamate ( Compound 2) Step 1 : [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-(5- aminopyrimidin -2- yl )-3- methyl - triazol -4- yl ] carbamate
在-78℃下,向(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物2B)(1.39 mmol)於四氫呋喃(14 mL)中之混合物中添加雙(三甲基矽烷基)醯胺鋰(1.53 mmol)於THF中之1 M溶液。10分鐘後,添加正丁基鋰(2.77 mmol)於己烷中之2.5 M溶液。45分鐘後,添加氯化鋅(4.30 mmol)於2-MeTHF中之1.9 M溶液,且在室溫下攪拌反應物45分鐘。此時,向反應物中添加與二氯甲烷(0.139 mmol)錯合之2-溴嘧啶-5-胺(1.94 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II),且將反應混合物加熱至70℃持續1小時。在反應完成之後,使混合物冷卻且用飽和氯化銨水溶液淬滅。用乙酸乙酯稀釋混合物,且分離有機物。用乙酸乙酯(3 × 10 mL)萃取水層。合併之有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由管柱層析純化以得到[(1R)-1-(2-氯-3-吡啶基)乙基] N-[5-(5-胺基嘧啶-2-基)-3-甲基-三唑-4-基]胺基甲酸酯。 步驟 2 : [(1R)-1-(2- 氯 -3- 吡啶基 ) 乙基 ]N-[5-[5-[(1- 氰基環丙烷羰基 ) 胺基 ] 嘧啶 -2- 基 ]-3- 甲基 - 三唑 -4- 基 ] 胺基甲酸酯 ( 化合物 2) To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (1.39 mmol) in tetrahydrofuran (14 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.53 mmol) in THF. After 10 min, a 2.5 M solution of n-butyllithium (2.77 mmol) in hexanes was added. After 45 min, a 1.9 M solution of zinc chloride (4.30 mmol) in 2-MeTHF was added and the reaction was stirred at room temperature for 45 min. At this point, 2-bromopyrimidin-5-amine (1.94 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (0.139 mmol) were added to the reaction, and the reaction mixture was heated to 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and quenched with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate, and the organics were separated. The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(5-aminopyrimidin-2-yl)-3-methyl-triazol-4-yl]carbamate. Step 2 : [(1R)-1-(2- chloro -3- pyridyl ) ethyl ]N-[5-[5-[(1- cyanocyclopropanecarbonyl ) amino ] pyrimidin -2- yl ]-3- methyl - triazol -4- yl ] carbamate ( Compound 2)
在室溫下攪拌[(1R)-1-(2-氯-3-吡啶基)乙基] N-[5-(5-胺基嘧啶-2-基)-3-甲基-三唑-4-基]胺基甲酸酯(0.08 mmol)、1-氰基環丙烷甲酸(0.096 mmol)及1-(3-二甲胺基丙基)-3-乙基碳二亞胺鹽酸鹽(0.096 mmol)於吡啶(1.0 mL)中之混合物30分鐘。反應完成後,在減壓下濃縮混合物。殘餘物係藉由逆相HPLC純化以得到[(1R)-1-(2-氯-3-吡啶基)乙基] N-[5-[5-[(1-氰基環丙烷羰基)胺基]嘧啶-2-基]-3-甲基-三唑-4-基]胺基甲酸酯。(MS(m/z ) 468.1[M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 9.04 (s, 2H), 8.30 (s, 1H), 8.00 (s, 1H), 7.45 (s, 1H), 6.08 (q, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.82 - 1.75 (m, 2H), 1.73 - 1.67 (m, 2H), 1.59 (s, 3H)。 實例 10 :製備化合物 3 及 4 A mixture of [(1R)-1-(2-chloro-3-pyridinyl)ethyl] N-[5-(5-aminopyrimidin-2-yl)-3-methyl-triazol-4-yl]carbamate (0.08 mmol), 1-cyanocyclopropanecarboxylic acid (0.096 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.096 mmol) in pyridine (1.0 mL) was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give [(1R)-1-(2-chloro-3-pyridyl)ethyl] N-[5-[5-[(1-cyanocyclopropanecarbonyl)amino]pyrimidin-2-yl]-3-methyl-triazol-4-yl]carbamate (MS ( m/z ) 468.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 9.04 (s, 2H), 8.30 (s, 1H), 8.00 (s, 1H), 7.45 (s, 1H), 6.08 (q, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.82 - 1.75 (m, 2H), 1.73 - 1.67 (m, 2H), 1.59 (s, 3H). Example 10 : Preparation of Compounds 3 and 4
化合物3及4一般根據流程B,步驟1合成。舉例而言,如下製備(R)-(1-甲基-4-(6-(3-甲基脲基)吡啶-3-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物3)。 Compounds 3 and 4 were generally synthesized according to Scheme B, step 1. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(6-(3-methylureido)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 3) was prepared as follows.
將1-甲基-3-(5-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡啶-2-基)脲(1.67 mmol)、(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(中間物2A)(0.556 mmol)及碳酸鈉(1.67 mmol)以3:1於1,4-二㗁烷/水(7 mL)中之混合物加熱至100℃持續1小時。將混合物冷卻且用水稀釋。用乙酸乙酯(3 × 10 mL)萃取混合物。合併之有機層經無水硫酸鈉乾燥且在減壓下濃縮。藉由逆相HPLC純化殘餘物以得到(R)-(1- 甲基 -4-(6-(3- 甲基脲基 ) 吡啶 -3- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 (化合物3)。(MS (m/z ) 432.1 [M+H]+ )。1H NMR (400 MHz, DMSO-d6) δ 10.05 (bs, 1H), 9.41 (bs, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.40 (bs, 1H), 8.03-7.85 (m, 3H), 7.54 (bs, 1H), 7.42 (d, J = 8.7 Hz, 1H), 5.93 (m, 1H), 3.85 (s, 3H), 2.75 (d, J = 4.2 Hz, 3H), 1.60 (bs, 3H)。 A mixture of 1-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl)urea (1.67 mmol), (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (0.556 mmol) and sodium carbonate (1.67 mmol) in 1,4-dioxane/water (7 mL) at a ratio of 3:1 was heated to 100 °C for 1 hour. The mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to obtain (R) -1-(2- chloropyridin -3- yl ) ethyl (1- methyl -4-(6-(3 -methylureido ) pyridin -3 - yl )-1H-1,2,3 - triazol -5- yl ) carbamate (Compound 3). (MS ( m/z ) 432.1 [M+H] + ). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (bs, 1H), 9.41 (bs, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.40 (bs, 1H), 8.03-7.85 (m, 3H), 7.54 (bs, 1H), 7.42 (d, J = 8.7 Hz, 1H), 5.93 (m, 1H), 3.85 (s, 3H), 2.75 (d, J = 4.2 Hz, 3H), 1.60 (bs, 3H).
化合物4類似地根據流程C,步驟2,藉由使(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物2B)(實例3)與1-乙基-3-(5-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡啶-2-基)脲遵循化合物3所描述之通用方法反應,得到(R)-(4-(6-(3-乙基脲基)吡啶-3-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物4)來製備。(MS (m/z ) 444.2 [M+H]+ )。1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.35 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.09 - 7.81 (m, 2H), 7.69 - 7.17 (m, 5H), 6.01 (m, 1H), 3.85 (s, 3H), 3.31 - 3.09 (m, 2H), 1.57 (bs, 3H), 1.11 (t, J = 7.2 Hz, 3H)。 實例 11 : 製備 [(1R)-1-(2- 氯 -3- 吡啶基 ) 乙基 ] N-[5-(5- 乙醯胺基 -6- 氟 -2- 吡啶基 )-3- 甲基 - 三唑 -4- 基 ] 胺基甲酸酯 ( 化合物 5) 步驟 1 : N-(6- 溴 -2- 氟 -3- 吡啶基 ) 乙醯胺 Compound 4 was prepared similarly according to Scheme C, step 2, by reacting 1-(2-chloropyridin-3-yl)ethyl (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (Example 3) with 1-ethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl)urea following the general method described for compound 3 to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(6-(3-ethylureido)pyridin-3-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 4). (MS ( m/z ) 444.2 [M+H] + ). 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.35 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.09 - 7.81 (m, 2H), 7.69 - 7.17 (m, 5H), 6.01 (m, 1H), 3.85 (s, 3H), 3.31 - 3.09 (m, 2H), 1.57 (bs, 3H), 1.11 (t, J = 7.2 Hz, 3H). Example 11 : Preparation of [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-(5- acetamido -6- fluoro -2- pyridinyl )-3- methyl - triazol -4- yl ] carbamate ( Compound 5) Step 1 : N-(6- bromo -2- fluoro -3- pyridyl ) acetamide
向6-溴-2-氟-吡啶-3-胺(5.24 mmol)於二氯甲烷(17 mL)中之溶液中添加吡啶(26.2 mmol),接著添加乙醯氯(22.9 mmol)。將反應物攪拌隔夜。反應完成後,用水稀釋混合物。用乙酸乙酯(3 × 10 mL)萃取混合物。合併之有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由管柱層析純化以得到N-(6-溴-2-氟-3-吡啶基)乙醯胺。 步驟 2 : 5-(5- 乙醯胺基 -6- 氟 -2- 吡啶基 )-3- 甲基 - 三唑 -4- 甲酸 To a solution of 6-bromo-2-fluoro-pyridin-3-amine (5.24 mmol) in dichloromethane (17 mL) was added pyridine (26.2 mmol) followed by acetyl chloride (22.9 mmol). The reaction was stirred overnight. After completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-(6-bromo-2-fluoro-3-pyridinyl)acetamide. Step 2 : 5-(5- Acetamido -6- fluoro -2- pyridinyl )-3 -methyl - triazole -4- carboxylic acid
將N-(6-溴-2-氟-3-吡啶基)乙醯胺(0.485 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(0.0485 mmol)、雙(頻哪醇根基)二硼(0.728 mmol)及乙酸鉀(0.728 mmol)於1,4-二㗁烷(5 mL)中之混合物加熱至100℃持續1小時。此時,將反應物冷卻至室溫,且將4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物1)(0.485 mmol)、碳酸鉀(0.971 mmol)及水(1.5 mL)添加至反應物中。用氮氣吹掃反應物且加熱至100℃持續1小時。反應完成後,使混合物冷卻且用水稀釋。用乙酸乙酯(3 × 10 mL)萃取混合物。合併之有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由逆相HPLC純化,得到5-(5-乙醯胺基-6-氟-2-吡啶基)-3-甲基-三唑-4-甲酸。 步驟 3 : [(1R)-1-(2- 氯 -3- 吡啶基 ) 乙基 ] N-[5-(5- 乙醯胺基 -6- 氟 -2- 吡啶基 )-3- 甲基 - 三唑 -4- 基 ] 胺基甲酸酯 ( 化合物 5) A mixture of N-(6-bromo-2-fluoro-3-pyridyl)acetamide (0.485 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (0.0485 mmol), bis(pinacolato)diboron (0.728 mmol) and potassium acetate (0.728 mmol) in 1,4-dioxane (5 mL) was heated to 100 °C for 1 hour. At this time, the reaction was cooled to room temperature and 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (0.485 mmol), potassium carbonate (0.971 mmol) and water (1.5 mL) were added to the reaction. The reaction was purged with nitrogen and heated to 100 °C for 1 hour. After completion of the reaction, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give 5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazole-4-carboxylic acid. Step 3 : [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-(5- acetamido -6- fluoro -2- pyridinyl )-3- methyl - triazol -4- yl ] carbamate ( Compound 5)
向5-(5-乙醯胺基-6-氟-2-吡啶基)-3-甲基-三唑-4-甲酸(0.372 mmol)、1-丙烷膦酸環酐(50%於DMF中,0.559 mmol)及疊氮基三甲基矽烷(0.559 mmol)酸於THF(1.9 mL)中之混合物中逐滴添加三乙胺(0.745 mmol)。添加(1R)-1-(2-氯-3-吡啶基)乙醇(0.559 mmol)且在70℃下加熱燒瓶1小時。反應完成後,使混合物冷卻且用水稀釋。用乙酸乙酯(3 × 10 mL)萃取混合物。合併之有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由逆相HPLC純化,得到[(1R)-1-(2-氯-3-吡啶基)乙基] N-[5-(5-乙醯胺基-6-氟-2-吡啶基)-3-甲基-三唑-4-基]胺基甲酸酯(化合物5)。(MS (m/z ) 434.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.54 (dd, J = 9.8, 8.3 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 6.09 (q, J = 6.4 Hz, 1H), 3.96 (s, 3H), 2.21 (s, 3H), 1.57 (d, J = 48.3 Hz, 3H)。 實例 12 : 製備 (R)-(4-(4- 胺基苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 中間物 8B) 步驟 1 : 4-(4-(( 三級丁氧基羰基 ) 胺基 ) 苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 To a mixture of 5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazole-4-carboxylic acid (0.372 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.559 mmol) and azidotrimethylsilane (0.559 mmol) acid in THF (1.9 mL) was added triethylamine (0.745 mmol) dropwise. (1R)-1-(2-chloro-3-pyridinyl)ethanol (0.559 mmol) was added and the flask was heated at 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give [(1R)-1-(2-chloro-3-pyridinyl)ethyl] N-[5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazol-4-yl]carbamate (Compound 5). (MS ( m/z ) 434.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.54 (dd, J = 9.8, 8.3 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 6.09 (q, J = 6.4 Hz, 1H), 3.96 (s, 3H), 2.21 (s, 3H), 1.57 (d, J = 48.3 Hz, 3H). Example 12 : Preparation of 1-(2- chloropyridin -3- yl ) ethyl (R)-(4-(4- aminophenyl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8B) Step 1 : 4-(4-(( tert-butyloxycarbonyl ) amino ) phenyl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid
向(4-((三級丁氧基羰基)胺基)苯基)硼酸(2.7 mmol)及4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物1)(2.4 mmol)之混合物中添加碳酸鉀(7.3 mmol)及Pd(PPh3 )4 (0.24 mmol)。將混合物懸浮於20 mL二㗁烷/水之10:1混合物中且用氬氣鼓泡5 min。將反應物密封且加熱至100℃持續16小時。反應物用1 M HCl水溶液及鹽水稀釋,且用乙酸乙酯(25 mL×2)萃取。合併之有機物經硫酸鈉乾燥,且濃縮。殘餘物係藉由矽膠管柱層析純化,得到4-(4-((三級丁氧基羰基)胺基)苯基)-1-甲基-1H-1,2,3-三唑-5-甲酸。 步驟 2 : (R)-(4-(4-(( 三級丁氧基羰基 ) 胺基 ) 苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 To a mixture of (4-((tert-butyloxycarbonyl)amino)phenyl)boronic acid (2.7 mmol) and 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (2.4 mmol) were added potassium carbonate (7.3 mmol) and Pd(PPh 3 ) 4 (0.24 mmol). The mixture was suspended in 20 mL of a 10:1 mixture of dioxane/water and bubbled with hydrogen for 5 min. The reaction was sealed and heated to 100° C. for 16 hours. The reaction was diluted with 1 M aqueous HCl and brine, and extracted with ethyl acetate (25 mL×2). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 4-(4-((tert-butyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 2 : (R)-1-(2- chloropyridin -3- yl ) ethyl (4-(4-(( tert-butyloxycarbonyl ) amino ) phenyl ) -1- methyl -1H-1,2,3- triazole - 5- yl ) carbamate
將4-(4-((三級丁氧基羰基)胺基)苯基)-1-甲基-1H-1,2,3-三唑-5-甲酸(1 mmol)、50% 1-丙烷膦酸酐溶液(1.4 mmol)於DMF中,且將疊氮基三甲基矽烷(1.4 mmol)懸浮於THF(3 mL)中。添加三乙胺(1.4 mmol)且使所得溶液在室溫下攪拌30 min。添加(1R)-1-(2-氯-3-吡啶基)乙醇(1.4 mmol)且在回流下加熱混合物12小時。將反應混合物冷卻至室溫,且在真空中移除THF。所得粗材料係藉由矽膠管柱層析純化,得到(R)-(4-(4-((三級丁氧基羰基)胺基)苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。 步驟 3 : (R)-(4-(4- 胺基苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 中間物 8B) 4-(4-((tributyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (1 mmol), 50% 1-propanephosphonic anhydride solution (1.4 mmol) were in DMF, and trimethylsilylazide (1.4 mmol) was suspended in THF (3 mL). Triethylamine (1.4 mmol) was added and the resulting solution was stirred at room temperature for 30 min. (1R)-1-(2-chloro-3-pyridinyl)ethanol (1.4 mmol) was added and the mixture was heated at reflux for 12 h. The reaction mixture was cooled to room temperature and the THF was removed in vacuo. The crude material was purified by silica gel column chromatography to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-((tributyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. Step 3 : 1-( 2- chloropyridin -3- yl ) ethyl (R)-(4-(4- aminophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8B)
將含4 M HCl之1,4-二㗁烷(1 mL)添加至(R)-(4-(4-((三級丁氧基羰基)胺基)苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.5 mmol)。將所得懸浮液在室溫下攪拌18 h。濃縮反應物,得到呈鹽酸鹽形式之(R)-(4-(4-胺基苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物8B)。 實例 13 : 製備 (R)- (4-(4- 乙醯胺基苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 6) 步驟 4 : (R)-(4-(4- 乙醯胺基苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 6) 4 M HCl in 1,4-dioxane (1 mL) was added to 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-((tributyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.5 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction was concentrated to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 8B). Example 13 : Preparation of (R)-(4-(4- acetamidophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 6) Step 4 : (R) -1-(2- chloropyridin -3- yl ) ethyl (4-(4- acetamidophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Compound 6)
將(R)-(4-(4-胺基苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物8B)鹽酸鹽(0.08 mmol)溶解於二氯甲烷(1 mL)、吡啶(0.2 mL)中。在室溫下逐滴添加乙醯氯(0.16 mmol)。30 min後,反應物經濃縮且溶解於四氫呋喃(2 mL)及0.5 M氫氧化鈉水溶液(2 mL)中,且劇烈攪拌10分鐘。將反應物用飽和氯化銨淬滅,且用乙酸乙酯(2 × 10 mL)萃取。將合併之有機物經硫酸鈉乾燥,濃縮,且藉由逆相HPLC純化,得到(R)-(4-(4-乙醯胺基苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物6)。(MS (m/z ) 415.08 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4) δ 8.36 (s, 1H), 8.06 (s, 1H), 7.65 (s, 4H), 7.56 - 6.99 (m, 1H), 6.11 (s, 1H), 3.95 (s, 3H), 2.17 (s, 3H), 1.82 - 1.19 (m, 3H)。 實例 14 : 製備 (R)-(4-(4-(( 甲氧基羰基 ) 胺基 ) 苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 7) (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8B) hydrochloride (0.08 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Acetyl chloride (0.16 mmol) was added dropwise at room temperature. After 30 min, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 min. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-acetamidophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 6). (MS ( m/z ) 415.08 [M+H] + ). 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.06 (s, 1H), 7.65 (s, 4H), 7.56 - 6.99 (m, 1H), 6.11 (s, 1H), 3.95 (s, 3H), 2.17 (s, 3H), 1.82 - 1.19 (m, 3H). Example 14 : Preparation of (R)-(4-(4-(( methoxycarbonyl ) amino ) phenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 7)
將(R)-(4-(4-胺基苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物8B)鹽酸鹽(0.08 mmol)溶解於二氯甲烷(1 mL)、吡啶(0.2 mL)中。在室溫下逐滴添加氯甲酸甲酯氯化物(0.16 mmol)。30分鐘後,反應物經濃縮且溶解於四氫呋喃(2 mL)及0.5 M氫氧化鈉水溶液(2 mL)中,且劇烈攪拌10分鐘。將反應物用飽和氯化銨淬滅,且用乙酸乙酯(2 × 10 mL)萃取。將合併之有機物經硫酸鈉乾燥,濃縮,且藉由逆相HPLC純化,得到(R)-(4-(4-甲氧基羰基)胺基)苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物7)。(MS (m/z ) 431.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4) δ 8.60 - 8.13 (m, 1H), 8.06 (s, 1H), 7.77 - 7.10 (m, 5H), 6.23 - 5.90 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 1.80 - 1.38 (m, 3H)。 實例 15 : 製備 (S)-2- 氟 -1- 苯基乙基 (4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸酯 ( 中間物 8D) 步驟 1 : (S)-(6-(5-(((2- 氟 -1- 苯基乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 吡啶 -3- 基 ) 胺基甲酸三級丁酯 (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8B) hydrochloride (0.08 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Methyl chloroformate chloride (0.16 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(4-methoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7). (MS ( m/z ) 431.1 [M+H] + ). 1H NMR (400 MHz, Methanol-d4) δ 8.60 - 8.13 (m, 1H), 8.06 (s, 1H), 7.77 - 7.10 (m, 5H), 6.23 - 5.90 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 1.80 - 1.38 (m, 3H). Example 15 : Preparation of (S)-2- fluoro -1- phenylethyl (4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8D) Step 1 : (S)-(6-(5-(((2- fluoro -1- phenylethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) carbamic acid tributyl ester
遵循描述於實例12中之用於製備(R)-(4-(4-((三級丁氧基羰基)胺基)苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯之步驟,使用(S)-2-氟-1-(3-氟苯基)乙-1-醇(0.73 mmol)代替(R)-1-(2-氯吡啶-3-基)乙-1-醇,得到(S)-(6-(5-(((2-氟-1-苯基乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺基甲酸三級丁酯。 步驟 2 : (S)-2- 氟 -1- 苯基乙基 (4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸酯 ( 中間物 8D) Following the procedure described in Example 12 for the preparation of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-((t-butyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, using (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol (0.73 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (S)-(6-(5-(((2-fluoro-1-phenylethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate was obtained. Step 2 : (S)-2- Fluoro -1- phenylethyl (4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8D)
將含4 M HCl之1,4-二㗁烷(1 mL)添加至(S)-(6-(5-(((2-氟-1-苯基乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺基甲酸三級丁酯(0.34 mmol)。將所得懸浮液在室溫下攪拌3 h。將反應物濃縮,得到呈鹽酸鹽形式之(S)-(4-(4-胺基苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-苯基乙酯(中間物8D)。 實例 16 : 製備 (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 8) 步驟 1 : (R)-(4-(5-(( 三級丁氧基羰基 ) 胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 4 M HCl in 1,4-dioxane (1 mL) was added to tributyl (S)-(6-(5-(((2-fluoro-1-phenylethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.34 mmol). The resulting suspension was stirred at room temperature for 3 h. The reaction was concentrated to give 2-fluoro-1-phenylethyl (S)-(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 8D). Example 16 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido ) pyrrolidone -2- yl ) -1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 8) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyrrolidone -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester
在-78℃下向(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物2B)(0.42 mmol)於3 mL THF中之溶液中逐滴添加1 N雙(三甲基矽基)胺基鋰於THF中之溶液(0.50 mmol,1 M)。15分鐘後,逐滴添加1.6 M正丁基鋰(nBuLi)於己烷(0.83 mmol)中之溶液。15分鐘後,逐滴添加1.9 M氯化鋅(ZnCl2 )於THF(1.0 mmol)中之溶液,且反應物在20分鐘內升溫至室溫。添加(5-溴吡𠯤-2-基)胺基甲酸三級丁酯(溴吡𠯤)(0.50 mmol)及(2-二環己基膦-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II)甲磺酸三級丁酯(XPhos Pd G3)(0.042 mmol)於THF中之溶液,且將反應物加熱至70℃持續2小時。隨後使反應物冷卻至室溫且用飽和NH4 Cl水溶液淬滅且用EtOAc萃取。將合併之有機層經Na2 SO4 乾燥且濃縮。藉由矽膠層析法(0-20% DCM/MeOH)純化得到(R)-(4-(5-((三級丁氧基羰基)胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。 步驟 2 : (R)-(4-(5- 胺基吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (0.42 mmol) in 3 mL THF was added 1 N lithium bis(trimethylsilyl)amide in THF (0.50 mmol, 1 M) dropwise at -78 °C. After 15 min, a solution of 1.6 M n-butyllithium (nBuLi) in hexanes (0.83 mmol) was added dropwise. After 15 min, a solution of 1.9 M zinc chloride (ZnCl 2 ) in THF (1.0 mmol) was added dropwise, and the reaction was allowed to warm to room temperature over 20 min. A solution of tributyl (5-bromopyridinium-2-yl)carbamate (bromopyridinium) (0.50 mmol) and tributyl (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) (0.042 mmol) in THF was added and the reaction was heated to 70 °C for 2 hours. The reaction was then cooled to room temperature and quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated. Purification by silica gel chromatography (0-20% DCM/MeOH) gave (R)-(4-(5-((tributyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2- chloropyridin -3-yl)ethyl ester. Step 2 : (R)-(4-(5- aminopyrrolidone -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester
在室溫下攪拌(R)-(4-(5-((三級丁氧基羰基)胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.126 mmol)於二㗁烷中之4N HCl中的溶液1小時。將反應物濃縮且置放於真空下隔夜,得到(R)-(4-(5-胺基吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。 步驟 3 : (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 8) A solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.126 mmol) in 4N HCl in dioxane was stirred at room temperature for 1 hour. The reaction was concentrated and placed under vacuum overnight to give 1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. Step 3 : (R)-(4-(5-(1- cyanocyclopropane -1- carboxamido ) pyrrolidone -2- yl )-1- methyl - 1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3 - yl ) ethyl ester ( Compound 8)
用吡啶(0.729 mmol)、1-氰基環丙烷-1-甲酸(0.114 mmol)及EDC (0.0875 mmol)處理(R)-(4-(5-胺基吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.0729 mmol)於0.2 mL DMF中之溶液且在室溫下攪拌3小時。用MeCN水溶液稀釋且藉由RP HPLC純化得到(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物27)。(MS(m/z ) 467.9[M+H]+)。1H NMR (400 MHz, 甲醇-d4) d 9.01 (s, 1H), 8.84 (s, 1H), 8.51-7.91 (m, 2H), 7.46 (s, 1H), 6.30 - 5.74 (m, 1H), 3.97 (s, 3H), 1.84 - 1.38 (m, 7H)。 實例 17 : 製備 (R)-(4-(5- 乙醯胺基 -3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 9) 步驟 1 : N-(6- 溴 -5- 氟 -3- 吡啶基 ) 乙醯胺 A solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0729 mmol) in 0.2 mL DMF was treated with pyridine (0.729 mmol), 1-cyanocyclopropane-1-carboxylic acid (0.114 mmol) and EDC (0.0875 mmol) and stirred at room temperature for 3 h. Dilution with aqueous MeCN and purification by RP HPLC gave 1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 27). (MS ( m/z ) 467.9 [M+H] +). 1H NMR (400 MHz, methanol-d4) d 9.01 (s, 1H), 8.84 (s, 1H), 8.51-7.91 (m, 2H), 7.46 (s, 1H), 6.30 - 5.74 (m, 1H), 3.97 (s, 3H), 1.84 - 1.38 (m, 7H). Example 17 : Preparation of (R)-(4-(5- acetamido -3- fluoropyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 9) Step 1 : N-(6- bromo -5- fluoro -3- pyridyl ) acetamide
向6-溴-5-氟-吡啶-3-胺(5.24 mmol)於二氯甲烷(17 mL)中之溶液中添加吡啶(26.2 mmol),接著添加乙醯氯(22.9 mmol)。將反應物攪拌隔夜。反應完成後,用水稀釋混合物。用乙酸乙酯(3 × 10 mL)萃取混合物。合併之有機層經無水硫酸鈉乾燥且在減壓下濃縮。殘餘物係藉由管柱層析純化以得到6-溴-5-氟-吡啶-3-胺。 步驟 2 : 4-(5- 乙醯胺 -3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 To a solution of 6-bromo-5-fluoro-pyridin-3-amine (5.24 mmol) in dichloromethane (17 mL) was added pyridine (26.2 mmol) followed by acetyl chloride (22.9 mmol). The reaction was stirred overnight. After completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-bromo-5-fluoro-pyridin-3-amine. Step 2 : 4-(5- Acetylamino -3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid
在-78℃下向4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物1)(1.3 mmol)於四氫呋喃(20 mL)中之混合物中添加雙(三甲基矽基)胺基鋰(1.3 mmol)於THF中之1 M溶液。10分鐘後,添加正丁基鋰(2.5 mmol)於己烷中之2.5 M溶液。45分鐘後,添加氯化鋅(2.5 mmol)於2-MeTHF中之1.9 M溶液,且使反應物升溫至室溫且攪拌30分鐘。反應混合物用氬氣鼓泡5分鐘,且隨後添加N-(6-溴-5-氟-3-吡啶基)乙醯胺(0.84 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)、二氯甲烷錯合物(0.08 mmol)。在70℃下加熱反應物2小時,其後使反應物冷卻且用1 M氯化氫水溶液(20 mL)稀釋。用乙酸乙酯(30 mL × 3)萃取反應混合物。將合併之有機層經硫酸鈉乾燥且濃縮,得到4-(5-乙醯胺基-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸,其未經進一步純化即用於下一步驟中。 步驟 3 : (R)-(4-(5- 乙醯胺基 -3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 9) To a mixture of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (1.3 mmol) in tetrahydrofuran (20 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.3 mmol) in THF. After 10 minutes, a 2.5 M solution of n-butyllithium (2.5 mmol) in hexanes was added. After 45 minutes, a 1.9 M solution of zinc chloride (2.5 mmol) in 2-MeTHF was added, and the reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was bubbled with argon for 5 minutes, and N-(6-bromo-5-fluoro-3-pyridyl)acetamide (0.84 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.08 mmol) were subsequently added. The reaction was heated at 70 °C for 2 hours, after which the reaction was cooled and diluted with 1 M aqueous hydrogen chloride solution (20 mL). The reaction mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give 4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, which was used in the next step without further purification. Step 3 : (R) -1-(2- chloropyridin -3- yl ) ethyl (4-(5- acetamido -3- fluoropyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Compound 9)
將DMF中之(R)-(4-(5-乙醯胺基-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.14 mmol)、50% 1-丙烷膦酸酐溶液(0.29 mmol),及疊氮基三甲基矽烷(0.29 mmol)懸浮於THF (2 mL)中。添加三乙胺(0.43 mmol)且使所得溶液在室溫下攪拌30分鐘。添加(1R)-1-(2-氯-3-吡啶基)乙醇(0.29 mmol)且在回流下加熱混合物4小時。將反應混合物冷卻至室溫,且在真空中移除THF。所得粗物質係藉由逆相HPLC純化,得到(R)-(4-(5-乙醯胺基-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物29)。(MS (m/z ) 434.0 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.52 (s, 1H), 8.33 (s, 1H), 8.19 - 7.76 (m, 2H), 7.48 (s, 1H), 6.20 - 5.90 (m, 1H), 4.01 (s, 3H), 2.21 (s, 3H), 1.60 (s, 3H)。 實例 18 : 製備 (R)-(4-(5- 胺基 -4- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 中間物 7B) 步驟 1 : (R)-(4-(5-(( 三級丁氧基羰基 ) 胺基 )-4- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.14 mmol), 50% 1-propanephosphonic anhydride solution (0.29 mmol), and trimethylsilylazide (0.29 mmol) in DMF were suspended in THF (2 mL). Triethylamine (0.43 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes. (1R)-1-(2-chloro-3-pyridinyl)ethanol (0.29 mmol) was added and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and the THF was removed in vacuo. The crude material was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29). (MS ( m/z ) 434.0 [M+H] + ). 1H NMR (400 MHz, Methanol- d4 ) δ 8.52 (s, 1H), 8.33 (s, 1H), 8.19 - 7.76 (m, 2H), 7.48 (s, 1H), 6.20 - 5.90 (m, 1H), 4.01 (s, 3H), 2.21 (s, 3H), 1.60 (s, 3H). Example 18 : Preparation of (R)-(4-(5- amino -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Intermediate 7B) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino )-4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3 - yl ) ethyl ester
在−78℃下向(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯、(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(中間物2A)(1 mmol)於四氫呋喃中(15 mL)之混合物中添加雙(三甲基矽基)胺基鋰(1.2 mmol)於四氫呋喃中之1 M溶液。10分鐘後,添加正丁基鋰(2.5 mmol)於己烷中之2.5 M溶液。45分鐘後,添加氯化鋅(2.5 mmol)於2-甲基四氫呋喃中之1.9 M溶液,且使反應物升溫至室溫且在室溫下攪拌30分鐘。將反應混合物用氬氣鼓泡5分鐘,且隨後添加(6-氯-4-氟吡啶-3-基)胺基甲酸三級丁酯(1.2 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)、二氯甲烷錯合物(0.1 mmol)。將反應混合物加熱至70℃持續1小時。反應完成後,將混合物冷卻且用1N鹽酸水溶液(20 mL)淬滅。用乙酸乙酯(3 × 10 mL)萃取水層。將合併之有機層經無水硫酸鈉乾燥且在減壓下濃縮以得到不經進一步純化即用於下一步驟中之(R)-(4-(5-((三級丁氧基羰基)胺基)-4-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。 步驟 2 : (R)-(4-(5- 胺基 -4- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 中間物 7B) To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (1 mmol) in tetrahydrofuran (15 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.2 mmol) in tetrahydrofuran at −78° C. After 10 minutes, a 2.5 M solution of n-butyllithium (2.5 mmol) in hexanes was added. After 45 minutes, a 1.9 M solution of zinc chloride (2.5 mmol) in 2-methyltetrahydrofuran was added, and the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was bubbled with hydrogen for 5 minutes, and then tributyl (6-chloro-4-fluoropyridin-3-yl)carbamate (1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.1 mmol) were added. The reaction mixture was heated to 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and quenched with 1N aqueous hydrochloric acid (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-(4-(5-((tributyloxycarbonyl)amino)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3- yl )ethyl ester which was used in the next step without further purification. Step 2 : (R)-(4-(5- amino -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2 - chloropyridin -3- yl ) ethyl ester ( Intermediate 7B)
將含4 M HCl之1,4-二㗁烷(1 mL)添加至(R)-(4-(5-((三級丁氧基羰基)胺基)-4-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.49 mmol)。將所得懸浮液在室溫下攪拌4小時。反應物經濃縮得到呈鹽酸鹽形式之(R)-(4-(5-胺基-4-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物7B)。 實例 19 : 製備 (R)-(4-(5- 乙醯胺基 -4- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 10) 4 M HCl in 1,4-dioxane (1 mL) was added to 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((tributyloxycarbonyl)amino)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.49 mmol). The resulting suspension was stirred at room temperature for 4 hours. The reaction was concentrated to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 7B). Example 19 : Preparation of (R)-(4-(5- acetamido -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 10)
將(R)-(4-(5-胺基-4-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物7B)(0.05 mmol)之鹽酸鹽溶解於二氯甲烷(1 mL)及吡啶(0.2 mL)中。在室溫下逐滴添加乙醯氯(0.1 mmol)。30分鐘後,反應物經濃縮且溶解於四氫呋喃(2 mL)及1 M氫氧化鈉水溶液(2 mL)中,且劇烈攪拌10分鐘。將反應物用飽和氯化銨淬滅,且用乙酸乙酯(2 × 10 mL)萃取。將合併之有機物經硫酸鈉乾燥,濃縮,且藉由逆相HPLC純化,得到(R)-(4-(5-乙醯胺基-4-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(化合物30) (MS (m/z ) 434.0 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 9.17 (d, J = 9.8 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J = 11.5 Hz, 1H), 7.48 (s, 1H), 6.18 - 6.00 (m, 1H), 3.99 (s, 3H), 2.24 (s, 3H), 1.62 (s, 3H)。 實例 20 : 製備 (R)-(4-(5-(( 三級丁氧基羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 11) The hydrochloride salt of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7B) (0.05 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Acetyl chloride (0.1 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-(4-(5-acetamido-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 30) (MS ( m/z ) 434.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 9.17 (d, J = 9.8 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J = 11.5 Hz, 1H), 7.48 (s, 1H), 6.18 - 6.00 (m, 1H), 3.99 (s, 3H), 2.24 (s, 3H), 1.62 (s, 3H). Example 20 : Preparation of 1-( 2- chloropyridin -3- yl ) ethyl (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl - 1H-1,2,3- triazol -5- yl ) carbamate ( Compound 11)
向4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(9.4 mmol)、1-丙烷膦酸環酐(50%於THF中,14.1 mmol)及疊氮基三甲基矽烷(14.1 mmol)酸於THF (100 mL)中之混合物中逐滴添加三乙胺(23.5 mmol)。將反應混合物在70℃下加熱1小時,隨後在相同溫度下添加(R)-1-(2-氯吡啶-3-基)乙-1-醇(18.8 mmol)。在加熱24小時之後,將反應物冷卻至室溫,濃縮且藉由矽膠層析純化以提供(R)-(4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(化合物11) (MS (m/z ) 474.12 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4) δ 8.67 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.94 (dd, J = 8.7, 2.6 Hz, 1H), 7.84 (dd, J = 8.6, 0.8 Hz, 1H), 7.47 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.75 - 1.46 (m, 12H)。 實例 21 :製備 (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 中間物 5A) To a mixture of 4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (9.4 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 14.1 mmol) and azidotrimethylsilane (14.1 mmol) acid in THF (100 mL) was added triethylamine (23.5 mmol) dropwise. The reaction mixture was heated at 70 °C for 1 hour, followed by the addition of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (18.8 mmol) at the same temperature. After heating for 24 hours, the reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to provide (R)-(4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 11) (MS ( m/z ) 474.12 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.67 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.94 (dd, J = 8.7, 2.6 Hz, 1H), 7.84 (dd, J = 8.6, 0.8 Hz, 1H), 7.47 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.75 - 1.46 (m, 12H). Example 21 : Preparation of 1-(2- chloropyridin -3- yl ) ethyl (R)-(4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 5A)
將含4 M HCl之1,4-二㗁烷(20 mL)添加至(R)-(4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(6.9 mmol)。將所得懸浮液在室溫下攪拌18小時。將反應物濃縮得到呈鹽酸鹽形式之(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物5A)。 實例 22 :製備 (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 中間物 5B) 步驟 1 : (R)-(6-(5-(((1-(2,5- 二氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 吡啶 -3- 基 ) 胺基甲酸三級丁酯 4 M HCl in 1,4-dioxane (20 mL) was added to 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (6.9 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction was concentrated to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 5A). Example 22 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Intermediate 5B) Step 1 : (R)-(6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) carbamic acid tributyl ester
向4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(10.6 mmol)、1-丙烷膦酸環酐(50%於THF中,16 mmol)及疊氮基三甲基矽烷(16 mmol)酸於THF(15 mL)中之混合物中逐滴添加三乙胺(27 mmol)。在70℃下加熱反應混合物0.5小時,隨後在相同溫度下添加(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇(21 mmol)。加熱24小時後,將反應物冷卻至室溫,濃縮且藉由矽膠層析純化,得到(R)-(6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺基甲酸三級丁酯。 步驟 2 : (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 中間物 5B) To a mixture of 4-(5-((tri-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (10.6 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 16 mmol) and azidotrimethylsilane (16 mmol) in THF (15 mL) was added triethylamine (27 mmol) dropwise. The reaction mixture was heated at 70 °C for 0.5 h, followed by the addition of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (21 mmol) at the same temperature. After heating for 24 hours, the reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to give (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamic acid tert-butyl ester. Step 2 : (R)-(4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Intermediate 5B)
將含4 M HCl之1,4-二㗁烷(15 mL)添加至(R)-(6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺基甲酸三級丁酯(4.2 mmol)。將所得懸浮液在室溫下攪拌18小時。將反應物濃縮,得到呈鹽酸鹽形式之(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B)。 實例 23 : 製備 (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 ( 中間物 5C) 4 M HCl in 1,4-dioxane (15 mL) was added to tributyl (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (4.2 mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to give 1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as the hydrochloride salt (Intermediate 5B). Example 23 : Preparation of (R) -1-(2- chloro -5- fluoropyridin -3- yl ) ethyl (4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 5C)
遵循描述於實例22中之製備(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B)的步驟,使用(R)-1-(2-氯-5-氟吡啶-3-基)乙-1-醇(1.7 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,得到(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(中間物5C)。 實例 24 : 製備 (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟吡啶 -3- 基 ) 乙酯 ( 中間物 5D) Following the procedure described in Example 22 for the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B), using (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (1.7 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5C) was obtained. Example 24 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Intermediate 5D)
遵循描述於實例22中之製備(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B),使用(R)-1-(2-氟吡啶-3-基)乙-1-醇(7.0 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,得到(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟吡啶-3-基)乙酯(中間物5D)。 實例 25 : 製備 (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 氟 -2- 甲基吡啶 -3- 基 ) 乙酯 ( 中間物 5E) Following the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) as described in Example 22, using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (7.0 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5D) was obtained. Example 25 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(5- fluoro -2- methylpyridin -3- yl ) ethyl ester ( Intermediate 5E)
遵循描述實例22於中之製備(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B),使用(R)-1-(5-氟-2-甲基吡啶-3-基)乙-1-醇(6.4 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,得到(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氟-2-甲基吡啶-3-基)乙酯(中間物5E)。 實例 26 : 製備 (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯苯基 ) 乙酯 ( 中間物 6A) The preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) was followed as described in Example 22, using (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethan-1-ol (6.4 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol to give (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5E). Example 26 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Intermediate 6A)
遵循描述於實例22中之製備(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-triazol-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B),使用(R)-1-(2-氯苯基)乙-1-醇(3.2 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,得到(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(中間物6A)。 實例 27 : 製備 (S)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 2- 氟 -1-(3- 氟苯基 ) 乙酯 ( 中間物 6B) Following the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) as described in Example 22, using (R)-1-(2-chlorophenyl)ethan-1-ol (3.2 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-chlorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) was obtained. Example 27 : Preparation of (S) -2- Fluoro - 1- (3- fluorophenyl ) ethyl (4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 6B)
遵循描述實例22於中之製備(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B),使用(S)-2-氟-1-(3-氟苯基)乙-1-醇(2.3 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,得到(S)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-(3-氟苯基)乙酯(中間物6B)。 實例 28 :製備 1-(2- 氯 -6- 氟吡啶 -3- 基 ) 乙 -1- 醇 Following the description of Example 22 for the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B), (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol (2.3 mmol) was used instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol to give 2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6B). Example 28 : Preparation of 1-(2- chloro -6- fluoropyridin - 3 -yl ) ethan -1- ol
將溶解於甲基四氫呋喃(20 ml)中之2-氯-6-氟菸鹼醛(2.51 mmol)在冰/乙腈浴中冷卻且隨後逐滴添加甲基溴化鎂溶液(3.0 M,7.20 mmol)。將反應混合物藉由添加乙醇淬滅,且隨後用乙酸乙酯稀釋並用10%檸檬酸洗滌。濃縮有機層。殘餘物係藉由管柱層析純化以得到1-(2-氯-6-氟吡啶-3-基)乙-1-醇。 實例 29 :製備 1-(2- 氟 -5- 甲基吡啶 -4- 基 ) 乙 -1- 醇: 2-Chloro-6-fluoronicotinaldehyde (2.51 mmol) dissolved in methyltetrahydrofuran (20 ml) was cooled in an ice/acetonitrile bath and then methylmagnesium bromide solution (3.0 M, 7.20 mmol) was added dropwise. The reaction mixture was quenched by adding ethanol and then diluted with ethyl acetate and washed with 10% citric acid. The organic layer was concentrated. The residue was purified by column chromatography to give 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol. Example 29 : Preparation of 1-(2- fluoro -5- methylpyridin -4- yl ) ethan -1- ol:
將2-氟-4-碘-5-甲基吡啶(4.22 mmol)於20 mL THF中之溶液冷卻至0℃且用1.6 M含nBuLi的己烷(5.06 mmol)處理。15分鐘後逐滴添加DMF(12.7 mmol)。攪拌反應物30 min,隨後升溫至室溫且用飽和NH4 Cl淬滅。混合物用EtOAc萃取,經MgSO4 乾燥且濃縮,得到2-氟-5-甲基異菸鹼醛。將2-氟-5-甲基異菸鹼醛(5.5 mmol)溶解於25 mL THF中且在丙酮冰浴中冷卻至-15℃。用3 M含MeMgBr之THF (11.2 mmol)處理且攪拌20分鐘。用飽和NH4 Cl淬滅且用EtOAc萃取,經MgSO4 乾燥,過濾且濃縮,得到1-(2-氟-5-甲基吡啶-4-基)乙-1-醇(MS(m/z) 155.9[M+H]+)。 實例 30 :製備 1-(2,5- 二氟吡啶 -4- 基 ) 乙 -1- 醇 A solution of 2-fluoro-4-iodo-5-methylpyridine (4.22 mmol) in 20 mL THF was cooled to 0 °C and treated with 1.6 M nBuLi in hexanes (5.06 mmol). DMF (12.7 mmol) was added dropwise after 15 min. The reaction was stirred for 30 min, then warmed to room temperature and quenched with saturated NH 4 Cl. The mixture was extracted with EtOAc, dried over MgSO 4 and concentrated to give 2-fluoro-5-methylisonicotinate aldehyde. 2-Fluoro-5-methylisonicotinate aldehyde (5.5 mmol) was dissolved in 25 mL THF and cooled to -15 °C in an acetone ice bath. Treated with 3 M MeMgBr in THF (11.2 mmol) and stirred for 20 min. Quenched with saturated NH 4 Cl and extracted with EtOAc, dried over MgSO 4 , filtered and concentrated to give 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol (MS (m/z) 155.9 [M+H]+). Example 30 : Preparation of 1-(2,5 -difluoropyridin -4- yl ) ethan -1- ol
遵循描述於實例29中之合成1-(2-氟-5-甲基吡啶-4-基)乙-1-醇的步驟,使用2,5-二氟異菸鹼醛(11.9 mmol)代替2-氟-5-甲基異菸鹼醛,得到1-(2,5-二氟吡啶-4-基)乙-1-醇。(MS (m/z) 160.11[M+H]+)。 實例 31 :製備 1-(5- 溴 -2- 氟吡啶 -3- 基 ) 乙 -1- 醇 Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 2,5-difluoroisonicotinaldehyde (11.9 mmol) was used instead of 2-fluoro-5-methylisonicotinaldehyde to give 1-(2,5-difluoropyridin-4-yl)ethan-1-ol. (MS (m/z) 160.11 [M+H]+). Example 31 : Preparation of 1-(5- bromo -2- fluoropyridin -3- yl ) ethan -1- ol
遵循描述於實例29中之合成1-(2-氟-5-甲基吡啶-4-基)乙-1-醇的步驟,使用5-溴-2-氟菸鹼醛(7.35 mmol)代替2-氟-5-甲基異菸鹼醛,得到1-(5-溴-2-氟吡啶-3-基)乙-1-醇。(MS (m/z) 220.01[M+H]+)。 實例 32 :製備 1-(5- 溴 -2- 氯吡啶 -3- 基 ) 乙 -1- 醇 Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 5-bromo-2-fluoronicotinate (7.35 mmol) was used instead of 2-fluoro-5-methylisonicotinate to give 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol. (MS (m/z) 220.01 [M+H]+). Example 32 : Preparation of 1-(5- bromo -2- chloropyridin -3- yl ) ethan -1- ol
遵循描述於實例29中之合成1-(2-氟-5-甲基吡啶-4-基)乙-1-醇的步驟,使用5-溴-2-氯菸鹼醛(10.6 mmol)代替2-氟-5-甲基異菸鹼醛,得到1-(5-溴-2-氯吡啶-3-基)乙-1-醇。(MS (m/z) 235.99[M+H]+)。 實例 33 :製備 1-(2,5- 二氟吡啶 -4- 基 ) 乙 -1- 醇 Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 5-bromo-2-chloronicotinaldehyde (10.6 mmol) was used instead of 2-fluoro-5-methylisonicotinaldehyde to give 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol. (MS (m/z) 235.99 [M+H]+). Example 33 : Preparation of 1-(2,5 -difluoropyridin -4- yl ) ethan -1- ol
遵循描述於實例29中之合成1-(2-氟-5-甲基吡啶-4-基)乙-1-醇的步驟,使用5-溴-2-氟菸鹼醛(7.4 mmol)代替2-氟-5-甲基異菸鹼醛,得到1-(5-溴-2-氟吡啶-3-基)乙-1-醇。(MS (m/z) 220.01[M+H]+)。 實例 34 : 製備 (4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -6- 氟吡啶 -3- 基 ) 乙酯 ( 中間物 5F) Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 5-bromo-2-fluoronicotinate (7.4 mmol) was used instead of 2-fluoro-5-methylisonicotinate to give 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol. (MS (m/z) 220.01 [M+H]+). Example 34 : Preparation of 1-(2- chloro -6- fluoropyridin -3- yl ) ethyl (4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol - 5- yl ) carbamate ( Intermediate 5F)
遵循描述於實例22中之製備(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B),使用1-(2-氯-6-氟吡啶-3-基)乙-1-醇(0.34 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,得到(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-6-氟吡啶-3-基)乙酯(中間物5F)。 實例 35 : 製備 (1- 甲基 -4-(5-(2,2,2- 三氟乙醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 溴 -2- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 12) 步驟 1 : (6-(5-(((1-(5- 溴 -2- 氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 吡啶 -3- 基 ) 胺基甲酸三級丁酯 Following the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) as described in Example 22, using 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol (0.34 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, 1-(2-chloro-6-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5F) was obtained. Example 35 : Preparation of 1-(5- bromo -2- fluoropyridin - 3- yl ) ethyl (1 - methyl -4-(5-(2,2,2 -trifluoroacetamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamate ( Compound 12) Step 1 : (6-(5-(((1-(5- bromo -2- fluoropyridin -3- yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) carbamic acid tributyl ester
將(6-(5-(((1-(5-溴-2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺基甲酸三級丁酯(0.125 mmol)於0.2 ML THF中之溶液用T3P (0.25 mmol)、疊氮基三甲基矽烷基(TMS-N3)(0.25 mmol)及三乙胺(TEA)(0.25 mmol)處理,且在室溫下攪拌20分鐘。添加1-(5-溴-2-氟吡啶-3-基)乙-1-醇於200 μL THF中之溶液且在65℃下加熱混合物90分鐘。混合物隨後用DCM稀釋且用NaHCO3水溶液洗滌,藉由矽膠層析純化得到(6-(5-(((1-(5-溴-2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺基甲酸三級丁酯。 步驟 2 : 2,2,2- 三氟乙酸、 6-(5-(((1-(5- 溴 -2- 氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 吡啶 -3- 銨鹽 A solution of tributyl (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.125 mmol) in 0.2 ML THF was treated with T3P (0.25 mmol), trimethylsilyl azide (TMS-N3) (0.25 mmol) and triethylamine (TEA) (0.25 mmol) and stirred at room temperature for 20 minutes. A solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol in 200 μL THF was added and the mixture was heated at 65° C. for 90 minutes. The mixture was then diluted with DCM and washed with aqueous NaHCO3 solution and purified by silica gel chromatography to give (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamic acid tert-butyl ester. Step 2 : 2,2,2- Trifluoroacetic acid, 6-(5-(((1-(5- bromo -2 - fluoropyridin -3- yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- ammonium salt
將(6-(5-(((1-(5-溴-2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺基甲酸三級丁酯(0.125 mmol)溶解於2 mL DCM及2 mL三氟乙酸(TFA)中。攪拌5分鐘,隨後濃縮。溶解於15 mL二氯乙烷中且再次濃縮。此重複2次,且所得油狀物留在高真空下隔夜。所獲得之2,2,2-三氟乙酸、6-(5-(((1-(5-溴-2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-銨鹽在下一步驟中以粗製形式使用。 步驟 3 : (1- 甲基 -4-(5-(2,2,2- 三氟乙醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 溴 -2- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 12) Tributyl (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.125 mmol) was dissolved in 2 mL DCM and 2 mL trifluoroacetic acid (TFA). Stirred for 5 minutes then concentrated. Dissolved in 15 mL dichloroethane and concentrated again. This was repeated 2 times and the resulting oil was left under high vacuum overnight. The obtained 2,2,2-trifluoroacetic acid and 6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl ) pyridine-3-ammonium salt were used in the next step in crude form. Step 3 : 1-( 5-bromo-2- fluoropyridin -3- yl ) ethyl ( 1 - methyl -4-(5-(2,2,2- trifluoroacetamido ) pyridin - 2- yl ) -1H -1,2,3 - triazol - 5- yl ) carbamate ( Compound 12)
2,2,2-三氟乙酸、6-(5-(((1-(5-溴-2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-銨鹽(0.125 mmol)溶解於2 mL DCM中且冷卻至0℃。用吡啶(0.36 mmol)及甲磺酸酐(0.156 mmol)處理此溶液。使其升溫至室溫且攪拌30分鐘。濃縮反應物且將殘餘物溶解於MeCN及水中。藉由RP HPLC純化得到(1-甲基-4-(5-(2,2,2-三氟乙醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-溴-2-氟吡啶-3-基)乙酯。(化合物12) (MS (m/z) 532.04 [M+H]+)。1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.85 (m, 1H), 8.37 - 8.32 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.7 Hz, 1H), 5.80 (s, 1H), 3.89 (s, 3H), 3.08 (s, 3H), 1.77 - 1.38 (m, 3H)。 實例 36 : 製備 (1- 甲基 -4-(5-(2,2,2- 三氟乙醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 溴 -2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 13) 2,2,2-Trifluoroacetic acid, 6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-ammonium salt (0.125 mmol) were dissolved in 2 mL DCM and cooled to 0 °C. This solution was treated with pyridine (0.36 mmol) and methanesulfonic anhydride (0.156 mmol). Allowed to warm to room temperature and stirred for 30 min. The reaction was concentrated and the residue was dissolved in MeCN and water. Purification by RP HPLC gave 1-(5-bromo-2-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 12) (MS (m/z) 532.04 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.85 (m, 1H), 8.37 - 8.32 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.7 Hz, 1H), 5.80 (s, 1H), 3.89 (s, 3H), 3.08 (s, 3H), 1.77 - 1.38 (m, 3H). Example 36 : Preparation of 1-(5- bromo -2- chloropyridin -3- yl ) ethyl (1- methyl -4-(5-(2,2,2- trifluoroacetamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamate ( Compound 13)
遵循描述於實例35中之合成(1-甲基-4-(5-(2,2,2-三氟乙醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-溴-2-氟吡啶-3-基)乙酯,使用1-(5-溴-2-氯吡啶-3-基)乙-1-醇(0.143 mmol)代替1-(5-溴-2-氟吡啶-3-基)乙-1-醇,得到(1-甲基-4-(5-(2,2,2-三氟乙醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-溴-2-氯吡啶-3-基)乙酯(化合物13)。(MS (m/z) 548.03 [M+H]+)。1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.94 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.38 (s, 1H), 5.84 (s, 1H), 3.91 (s, 3H), 1.58 (s, 3H)。 實例 37 : 製備 (R)-(4-(5- 乙醯胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 氯 -2- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 14) 步驟 1 : (R)-(4-(5-(( 三級丁氧基羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 氯 -2- 氟吡啶 -3- 基 ) 乙酯 Following the synthesis of 1-(5-bromo-2-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate described in Example 35, 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol (0.143 mmol) was used instead of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol to give 1-(5-bromo-2-chloropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 13). (MS (m/z) 548.03 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.94 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.38 (s, 1H), 5.84 (s, 1H), 3.91 (s, 3H), 1.58 (s, 3H). Example 37 : Preparation of 1-( 5- chloro -2 - fluoropyridin -3- yl ) ethyl (R)-(4-(5- acetamidopyridin - 2- yl )-1 - methyl - 1H -1,2,3- triazol -5- yl ) carbamate ( Compound 14) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(5- chloro -2- fluoropyridin -3- yl ) ethyl ester
遵循描述於實例35,步驟1中之合成(1-甲基-4-(5-(2,2,2-三氟乙醯胺基)吡啶-2-)-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-溴-2-氟吡啶-3-基)乙酯的步驟,使用(R)-1-(5-氯-2-氟吡啶-3-基)乙-1-醇(0.43 mmol)代替1-(5-溴-2-氟吡啶-3-基)乙-1-醇,得到(R)-(4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氯-2-氟吡啶-3-基)乙酯。(MS (m/z) 492.03 [M+H]+)。 步驟 2 : (R)-(4-(5- 胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 氯 -2- 氟吡啶 -3- 基 ) 乙酯鹽酸鹽 Following the procedure described in Example 35, step 1 for the synthesis of 1-(5-bromo-2-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-)-1H-1,2,3-triazol-5-yl)carbamate, using (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethan-1-ol (0.43 mmol) instead of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol, (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl (4-(5-((tri-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was obtained. (MS (m/z) 492.03 [M+H]+). Step 2 : (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(5- chloro -2- fluoropyridin -3- yl ) ethyl ester hydrochloride
將(R)-(4-(5-((三級丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氯-2-氟吡啶-3-基)乙酯(0.193 mmol)於含4N HCl的二㗁烷中之溶液在室溫下攪拌1小時。將反應物濃縮且置放於真空下隔夜,得到呈油狀之(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氯-2-氟吡啶-3-基)乙酯鹽酸鹽。 步驟 3 : (R)-(4-(5- 乙醯胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(5- 氯 -2- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 14) A solution of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-((tri-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.193 mmol) in 4N HCl in dioxane was stirred at room temperature for 1 hour. The reaction was concentrated and placed under vacuum overnight to give (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride as an oil. Step 3 : (R) -1-(5- chloro -2- fluoropyridin -3 - yl ) ethyl (4-(5- acetamidopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Compound 14)
將(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氯-2-氟吡啶-3-基)乙酯鹽酸鹽(0.193 mmol)於0.5 mL DCM中之溶液用吡啶(2.9 mmol)處理且冷卻至0℃。添加乙醯氯(0.212 mmol)且在0℃下攪拌混合物45分鐘。在真空中濃縮反應物且藉由RP HPLC純化,得到(R)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氯-2-氟吡啶-3-基)乙酯。(化合物14) (MS (m/z) 434.0 [M+H]+)。H NMR (400 MHz, 乙腈-d3) δ 8.98 - 8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24 - 8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62 - 1.55 (m, 3H)。 實例 38 : 製備 (R)-(4-(5- 乙醯胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 15) A solution of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.193 mmol) in 0.5 mL DCM was treated with pyridine (2.9 mmol) and cooled to 0 °C. Acetyl chloride (0.212 mmol) was added and the mixture was stirred at 0 °C for 45 min. The reaction was concentrated in vacuo and purified by RP HPLC to give 1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 14) (MS (m/z) 434.0 [M+H]+). H NMR (400 MHz, acetonitrile-d3) δ 8.98 - 8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24 - 8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62 - 1.55 (m, 3H). Example 38 : Preparation of (R)-(4-(5- acetamidopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester ( Compound 15)
遵循描述於實例39,步驟3中之合成(R)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氯-2-氟吡啶-3-基)乙酯的步驟,使用(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(0.23 mmol),代替(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氯-2-氟吡啶-3-基)乙酯,得到(R)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(化合物15)。(MS (m/z) 434.0 [M+H]+) H NMR (400 MHz, 乙腈-d3) δ 8.98 - 8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24 - 8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62 - 1.55 (m, 3H)。 實例 39 : 製備 (R)-(4-(5- 甲醯胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 16) The synthesis of 1-(5-chloro-2-fluoropyridin-3-yl)ethyl (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.23 mmol), instead of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-chloro-2-fluoropyridin-3-yl)ethyl ester, to obtain (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester (Compound 15). (MS (m/z) 434.0 [M+H]+) H NMR (400 MHz, acetonitrile-d3) δ 8.98 - 8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24 - 8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62 - 1.55 (m, 3H). Example 39 : Preparation of (R)-(4-(5- carboxamidopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 16)
在室溫下在氬氣氛圍下向乙酸酐(3 mmol)添加甲酸(5 mmol)。將反應混合物在室溫下攪拌30分鐘。隨後在室溫下將THF(0.33 mL)中之(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(中間物5A)(0.37 mmol)添加至反應混合物。在60℃下攪拌反應混合物1小時。將反應混合物濃縮至乾燥,且隨後與甲苯共蒸發。殘餘物係藉由逆相HPLC純化,得到(R)-(4-(5-甲醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(化合物41) (MS (m/z ) 402.0 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.89 (d, 1H), 8.37 (d, 2H), 8.19 - 8.03 (m, 1H), 8.02 - 7.89 (m, 1H), 7.80 - 7.59 (m, 1H), 7.49 (s, 1H), 6.09 (m, 1H), 4.00 (d, 3H), 1.63 (s, 3H)。 實例 40 : 製備 (R)-(4-(5-(( 甲氧羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 17) To acetic anhydride (3 mmol) was added formic acid (5 mmol) under an atmosphere of argon at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. Then (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.37 mmol) in THF (0.33 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated to dryness and then co-evaporated with toluene. The residue was purified by reverse phase HPLC to give (R)-(4-(5-carboxamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 41) (MS ( m/z ) 402.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.89 (d, 1H), 8.37 (d, 2H), 8.19 - 8.03 (m, 1H), 8.02 - 7.89 (m, 1H), 7.80 - 7.59 (m, 1H), 7.49 (s, 1H), 6.09 (m, 1H), 4.00 (d, 3H), 1.63 (s, 3H). Example 40 : Preparation of 1-(2-chloropyridin-3-yl)ethyl (R)-( 4- (5-(( methoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl - 1H-1,2,3 - triazol - 5 - yl ) carbamate ( Compound 17 )
將(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(中間物5A)(0.78 mmol)溶解於二氯甲烷(1 mL)、吡啶(0.2 mL)中。在室溫下逐滴添加氯甲酸甲酯氯化物(0.14 mmol)。30分鐘後,反應物經濃縮且溶解於四氫呋喃(2 mL)及0.5 M氫氧化鈉水溶液(2 mL)中,且劇烈攪拌10分鐘。將反應物用飽和氯化銨淬滅,且用乙酸乙酯(2 × 10 mL)萃取。將合併之有機物經硫酸鈉乾燥,濃縮,且藉由逆相HPLC純化,得到(R)-(4-(5-((甲氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(化合物17) (MS (m/z ) 432.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.70 (s, 1H), 8.31 (s, 1H), 8.13 - 7.92 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 6.21 - 5.92 (m, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 1.61 (s, 3H)。 實例 41 : 製備 (S)-(4-(4-(( 甲氧羰基 ) 胺基 ) 苯基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 2- 氟 -1- 苯基乙酯 ( 化合物 18) (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.78 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Methyl chloroformate chloride (0.14 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 17) (MS ( m/z ) 432.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.70 (s, 1H), 8.31 (s, 1H), 8.13 - 7.92 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 6.21 - 5.92 (m, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 1.61 (s, 3H). Example 41 : Preparation of 2-fluoro -1- phenylethyl (S)-(4-(4-(( methoxycarbonyl ) amino ) phenyl )-1- methyl - 1H-1,2,3 - triazol -5 - yl ) carbamate ( Compound 18 )
遵循描述於實例40中之合成(R)-(4-(5-((甲氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯的步驟,使用(S)-(4-(4-胺基苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-苯基乙酯(中間物8D)(0.06 mmol)代替(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯,得到(S)-(4-(4-((甲氧羰基)胺基)苯基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-苯基乙酯。(化合物18) (MS (m/z ) 414.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 7.87 - 6.82 (m, 9H), 6.03 (s, 1H), 4.81 - 4.56 (m, 2H), 3.92 (s, 3H), 3.78 (s, 3H)。 實例 42 : 製備 (S)-(4-(5-(( 甲氧羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 2- 氟 -1-(3- 氟苯基 ) 乙酯 ( 化合物 19) The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 2-fluoro-1-phenylethyl (4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8D) (0.06 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate with 1-(2-chloropyridin-3-yl)ethyl ester to give (S)-(4-(4-((methoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 18) (MS ( m/z ) 414.1 [M+H] + ). 1H NMR (400 MHz, Methanol- d4 ) δ 7.87 - 6.82 (m, 9H), 6.03 (s, 1H), 4.81 - 4.56 (m, 2H), 3.92 (s, 3H), 3.78 (s, 3H). Example 42 : Preparation of (S)-(4-(5-(( methoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 2- fluoro -1-(3- fluorophenyl ) ethyl ester ( Compound 19)
遵循描述於實例40中之合成(R)-(4-(5-((甲氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯的步驟,使用(S)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-(3-氟苯基)乙酯(中間物6B)(0.05 mmol)代替(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯,得到(S)-(4-(5-((甲氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-(3-氟苯基)乙酯。(化合物19) (MS (m/z ) 433.2 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.69 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 - 6.62 (m, 4H), 6.09 - 5.77 (m, 1H), 4.80 - 4.47 (m, 2H), 3.97 (s, 3H), 3.79 (s, 3H)。 實例 43 : 製備 (R)-(4-(5-(( 甲氧羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯苯基 ) 乙酯 ( 化合物 20) The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 2-fluoro-1-(3-fluorophenyl)ethyl (S)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6B) (0.05 mmol) was used to replace (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate to obtain (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 19) (MS ( m/z ) 433.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.69 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 - 6.62 (m, 4H), 6.09 - 5.77 (m, 1H), 4.80 - 4.47 (m, 2H), 3.97 (s, 3H), 3.79 (s, 3H). Example 43 : Preparation of (R)-(4-(5-(( methoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Compound 20)
遵循描述於實例40中之合成(R)-(4-(5-((甲氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯的步驟,使用(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(中間物6A)(0.03 mmol)代替(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-)胺基甲酸1-(2-氯吡啶-3-基)乙酯,得到(R)-(4-(5-((甲氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(化合物20)。(MS (m/z ) 431.2 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.74 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.74 - 7.00 (m, 4H), 6.14 (d, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.42 (s, 3H)。 實例 44 : 製備 (R)-(4-(5-(( 乙氧羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 21) The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 1-(2-chlorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) (0.03 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate with 1-(2-chloropyridin-3-yl)ethyl to give (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate with 1-(2-chlorophenyl)ethyl (Compound 20). (MS ( m/z ) 431.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.74 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.74 - 7.00 (m, 4H), 6.14 (d, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.42 (s, 3H). Example 44 : Preparation of 1-(2-chloropyridin-3-yl) ethyl (R)-(4-(5-(( ethoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl - 1H -1,2,3- triazol - 5 - yl ) carbamate ( Compound 21 )
將懸浮於二氯甲烷(1 mL)中之(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(中間物5A)(0.10 mmol)用N,N-二異丙基乙胺(30 µL,0.17 mmol)處理,接著用氯甲酸乙酯(0.210 mmol)處理。在室溫下攪拌反應混合物15分鐘。濃縮反應混合物。在HPLC上純化殘餘物且藉由凍乾器乾燥溶離份。將凍乾固體溶解於甲基四氫呋喃(1 mL)中且用1 N氫氧化鈉溶液(400 µL)處理。在55℃下加熱反應混合物30分鐘。在冷卻至室溫之後,濃縮反應混合物。在HPLC上純化殘餘物以提供(R)-(4-(5-((乙氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物21)。(MS (m/z ) 446.0 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.80 (s, 1H), 8.34 (s, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.65 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H)。 實例 45 : 製備 (R)-(4-(5-(( 異丁氧基羰基 ) 胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 22) (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.10 mmol) suspended in dichloromethane (1 mL) was treated with N,N-diisopropylethylamine (30 µL, 0.17 mmol) followed by ethyl chloroformate (0.210 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated. The residue was purified on HPLC and the elution fraction was dried by lyophilization. The lyophilized solid was dissolved in methyltetrahydrofuran (1 mL) and treated with 1 N sodium hydroxide solution (400 µL). The reaction mixture was heated at 55 °C for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified on HPLC to provide (R)-(4-(5-((ethoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 21). (MS ( m/z ) 446.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.80 (s, 1H), 8.34 (s, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.65 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). Example 45 : Preparation of (R)-(4-(5-(( isobutoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 22)
遵循描述於實例44中之合成(R)-(4-(5-((乙氧羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯的步驟,使用氯甲酸異丁酯(0.2 mmol)代替氯甲酸甲酯,得到(R)-(4-(5-((異丁氧基羰基)胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物22)。(MS (m/z ) 474.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.84 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 6.09 (d, J = 7.1 Hz, 1H), 4.01 (d, J = 6.7 Hz, 2H), 4.00 (s, 4H), 2.04 (dq, J = 13.4, 6.7 Hz, 1H), 1.65 (s, 3H), 1.03 (d, J = 6.7 Hz, 6H)。 實例 46 :製備 (R)-(4-(5- 乙醯胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 23) Following the procedure described in Example 44 for the synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((ethoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, isobutyl chloroformate (0.2 mmol) was used instead of methyl chloroformate to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((isobutoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 22). (MS ( m/z ) 474.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.84 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 6.09 (d, J = 7.1 Hz, 1H), 4.01 (d, J = 6.7 Hz, 2H), 4.00 (s, 4H), 2.04 (dq, J = 13.4, 6.7 Hz, 1H), 1.65 (s, 3H), 1.03 (d, J = 6.7 Hz, 6H). Example 46 : Preparation of (R)-(4-(5- acetamidopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 23)
將(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物5A)(0.07 mmol)之鹽酸鹽溶解於二氯甲烷(1 mL)及吡啶(0.2 mL)中。在室溫下逐滴添加乙醯氯(0.14 mmol)。30 min後,反應物經濃縮且溶解於四氫呋喃(2 mL)及1 M氫氧化鈉水溶液(2 mL)中,且劇烈攪拌10分鐘。將反應物用飽和氯化銨淬滅,且用乙酸乙酯(2 × 10 mL)萃取。將合併之有機物經硫酸鈉乾燥,濃縮,且藉由逆相HPLC純化,得到(R)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(化合物23) (MS (m/z ) 416.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.83 (s, 1H), 8.31 (s, 1H), 8.21 - 7.95 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 6.08 (m, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 1.61 (s, 3H)。 實例 47 : 製備 (R)-(4-(5- 乙醯胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯苯基 ) 乙酯 ( 化合物 24) The hydrochloride salt of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A) (0.07 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Acetyl chloride (0.14 mmol) was added dropwise at room temperature. After 30 min, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 min. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 23) (MS ( m/z ) 416.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.83 (s, 1H), 8.31 (s, 1H), 8.21 - 7.95 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 6.08 (m, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 1.61 (s, 3H). Example 47 : Preparation of (R)-(4-(5- acetamidopyridin -2- yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Compound 24)
遵循描述於實例46中之合成(R)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯的步驟,使用(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(中間物6A)(0.03 mmol)代替(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯,得到(R)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯苯基)乙酯(化合物24)。(MS (m/z ) 415.2 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.88 (s, 1H), 8.10 (dd, J = 8.6, 2.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.71 - 7.05 (m, 4H), 6.29 - 5.90 (m, 1H), 3.96 (s, 3H), 2.18 (s, 3H), 1.55 (s, 3H)。 實例 48 : 製備 (S)-(4-(5- 乙醯胺基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 2- 氟 -1-(3- 氟苯基 ) 乙酯 ( 化合物 25) The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 1-(2-chlorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) (0.03 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester to obtain (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chlorophenyl)ethyl ester (Compound 24). (MS ( m/z ) 415.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.88 (s, 1H), 8.10 (dd, J = 8.6, 2.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.71 - 7.05 (m, 4H), 6.29 - 5.90 (m, 1H), 3.96 (s, 3H), 2.18 (s, 3H), 1.55 (s, 3H). Example 48 : Preparation of 2- fluoro - 1- (3- fluorophenyl ) ethyl (S)-(4-(5- acetamidopyridin -2 - yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Compound 25 )
遵循描述於實例46中之合成(R)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯的步驟,使用(S)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-(3-氟苯基)乙酯(中間物6B)(0.05 mmol)代替(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-胺基甲酸1-(2-氯吡啶-3-基)乙酯,得到(S)-(4-(5-乙醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-(3-氟苯基)乙酯。(化合物25) (MS (m/z ) 417.2 [M+H]+ )。1H NMR (400 MHz, 甲醇-d4) δ 8.89 (s, 1H), 8.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.56 - 6.58 (m, 4H), 6.11 - 5.70 (m, 1H), 4.79 - 4.30 (m, 2H), 3.98 (s, 3H), 2.18 (s, 3H)。 實例 49 : 製備 (4-(5-(3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟 -5- 甲基吡啶 -4- 基 ) 乙酯 ( 化合物 26) 步驟 1 : 4-(5-(3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸甲酯 The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 2-fluoro-1-(3-fluorophenyl)ethyl (S)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6B) (0.05 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester to obtain (S)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)carbamic acid 2-fluoro-1-(3-fluorophenyl)ethyl ester. (Compound 25) (MS ( m/z ) 417.2 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.56 - 6.58 (m, 4H), 6.11 - 5.70 (m, 1H), 4.79 - 4.30 (m, 2H), 3.98 (s, 3H), 2.18 (s, 3H). Example 49 : Preparation of 1-( 2-fluoro- 5- methylpyridin -4 -yl ) ethyl (4-(5-(3,3- difluorocyclobutane - 1- carboxamido ) pyridin -2- yl )-1- methyl - 1H -1,2,3 - triazol - 5- yl ) carbamate ( Compound 26 ) Step 1 : 4-(5-(3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester
向4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯鹽酸鹽(中間物3A)(4.3 mmol)於DCM:吡啶(25 mL)之5:1混合物中之混合物添加3,3-二氟環丁烷-1-甲酸(5.1 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(5.1 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時將反應物濃縮以得到直接用於下一步驟之粗4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯。 步驟 2 : 4-(5-(3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 To a mixture of methyl 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate hydrochloride (Intermediate 3A) (4.3 mmol) in a 5:1 mixture of DCM:pyridine (25 mL) was added 3,3-difluorocyclobutane-1-carboxylic acid (5.1 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.1 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 hours, at which time the reaction was concentrated to give crude methyl 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate which was used directly in the next step. Step 2 : 4-(5-(3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid
將粗4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯(4.3 mmol)用2 M NaOH水溶液(50 mL)及THF (25 mL)處理,且劇烈攪拌30分鐘。接下來,用濃HCl處理反應物,直至pH=5。沈澱物經過濾且在真空下乾燥以得到未經進一步純化即用於下一步驟中之4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸。 步驟 3 : (4-(5-(3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟 -5- 甲基吡啶 -4- 基 ) 乙酯 ( 化合物 26) Crude 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester (4.3 mmol) was treated with 2 M aqueous NaOH (50 mL) and THF (25 mL) and stirred vigorously for 30 min. Next, the reaction was treated with concentrated HCl until pH = 5. The precipitate was filtered and dried under vacuum to give 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid which was used in the next step without further purification. Step 3 : 1- ( 2-fluoro-5-methylpyridin - 4 - yl ) ethyl (4-(5-(3,3- difluorocyclobutane -1 -carboxamido ) pyridin -2- yl ) -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Compound 26 )
將4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(0.0889 mmol)於100 μL DMF中之溶液用50%於DMF(0.178 mmol) TMS-N3(0.156 mmol)及TEA(0.267 mmol)中之T3P處理,且攪拌混合物20分鐘。添加1-(2-氟-5-甲基吡啶-4-基)乙-1-醇(0.156 mmol)且在65℃下加熱反應物2小時。將反應物冷卻至室溫且藉由RP HPLC純化以得到(4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟-5-甲基吡啶-4-基)乙酯(化合物26)。(MS (m/z) 490.04) [M+H]+) 1H NMR (400 MHz, 乙腈-d3) δ 9.00 - 8.89 (m, 1H), 8.88 - 8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J = 9.1, 5.8, 2.8 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.18 - 3.06 (m, 1H), 3.02 - 2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H)。 實例 50 : 製備 (4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟 -5- 甲基吡啶 -4- 基 ) 乙酯 ( 化合物 27) 步驟 1 : 4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸甲酯 A solution of 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.0889 mmol) in 100 μL DMF was treated with 50% T3P in DMF (0.178 mmol) TMS-N3 (0.156 mmol) and TEA (0.267 mmol) and the mixture was stirred for 20 min. 1-(2-Fluoro-5-methylpyridin-4-yl)ethan-1-ol (0.156 mmol) was added and the reaction was heated at 65 °C for 2 h. The reaction was cooled to room temperature and purified by RP HPLC to give 1-(2-fluoro-5-methylpyridin-4-yl)ethyl (4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 26). (MS (m/z) 490.04) [M+H]+) 1H NMR (400 MHz, ACN-d3) δ 9.00 - 8.89 (m, 1H), 8.88 - 8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J = 9.1, 5.8, 2.8 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.18 - 3.06 (m, 1H), 3.02 - 2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H). Example 50 : Preparation of 1-(2 - fluoro -5 -methylpyridin -4 - yl ) ethyl (4-(5-(1- cyanocyclopropane -1-carboxamido) pyridin -2- yl )-1 - methyl -1H-1,2,3 - triazol - 5 - yl ) carbamate ( Compound 27 ) Step 1 : 4-(5-(1 -cyanocyclopropane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester
遵循描述於實例49,步驟1中之合成4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯的步驟,使用1-氰基環丙烷-1-甲酸(5.1 mmol)代替3,3-二氟環丁烷-1-甲酸,得到4-(5-(1-氰基環丙烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯。 步驟 2 : 4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 Following the procedure described in Example 49, Step 1 for the synthesis of methyl 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate, 1-cyanocyclopropane-1-carboxylic acid (5.1 mmol) was used instead of 3,3-difluorocyclobutane-1-carboxylic acid to give methyl 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate. Step 2 : 4-(5-(1- cyanocyclopropane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5- carboxylic acid
遵循描述於實例49,步驟2中之合成4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸的步驟,使用4-(5-(1-氰基環丙烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯(5.1 mmol)代替4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸甲酯,得到4-(5-(1-氰基環丙烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸。 步驟 3 : (4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟 -5- 甲基吡啶 -4- 基 ) 乙酯 ( 化合物 27) Following the procedure described in Example 49, Step 2 for the synthesis of 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, methyl 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (5.1 mmol) was used to replace 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester to obtain 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2- yl )-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 3 : 1-(2- fluoro -5- methylpyridin -4-yl ) ethyl (4-(5-(1- cyanocyclopropane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5- yl ) carbamate ( Compound 27 )
遵循描述於實例49,步驟3中之合成(4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟-5-甲基吡啶-4-基)乙酯,使用4-(5-(1-氰基環丙烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(0.0961 mmol)代替4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸,得到4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(化合物27)。(MS (m/z) 465.12 [M+H]+)。1H NMR (400 MHz, 乙腈-d3) δ 9.00 - 8.89 (m, 1H), 8.88 - 8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J = 9.1, 5.8, 2.8 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.18 - 3.06 (m, 1H), 3.02 - 2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H)。 實例 51 : 製備 (R)-(4-(5-(3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 28) The synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethyl (4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed as described in Example 49, Step 3, using 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.0961 mmol) was used to replace 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid to obtain 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Compound 27). (MS (m/z) 465.12 [M+H]+). 1H NMR (400 MHz, acetonitrile-d3) δ 9.00 - 8.89 (m, 1H), 8.88 - 8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J = 9.1, 5.8, 2.8 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.18 - 3.06 (m, 1H), 3.02 - 2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H). Example 51 : Preparation of (R)-(4-(5-(3,3 -difluorocyclobutane -1 -carboxamido ) pyridin -2 - yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 28)
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物5B)(0.07 mmol)於吡啶(0.5 mL)中之混合物中添加3,3-二氟環丁烷羰基氯化物(0.07 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-(3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物28)。(MS (m/z ) 494.1 [M+H]+ )。1H NMR (400 MHz, 甲醇-d4) δ 8.79 (s, 1H), 8.21 - 7.67 (m, 4H), 5.95 (s, 1H), 4.00 (s, 3H), 3.21 - 3.05 (m, 1H), 3.05 - 2.68 (m, 4H), 1.62 (s, 3H)。 實例 52 :製備化合物 29 至 37 To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) (0.07 mmol) in pyridine (0.5 mL) was added 3,3-difluorocyclobutanecarbonyl chloride (0.07 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 28). (MS ( m/z ) 494.1 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.21 - 7.67 (m, 4H), 5.95 (s, 1H), 4.00 (s, 3H), 3.21 - 3.05 (m, 1H), 3.05 - 2.68 (m, 4H), 1.62 (s, 3H). Example 52 : Preparation of compounds 29 to 37
化合物29至37一般根據流程C,步驟4合成。舉例而言,如下製備(R)-(4-(5-苯甲醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物29)。 Compounds 29 to 37 were generally synthesized according to Scheme C, step 4. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-benzamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29) was prepared as follows.
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(中間物5A)(0.07 mmol)於吡啶(0.5 mL)中之混合物中添加苯甲醯氯(0.07 mmol)。使反應混合物在磁性攪拌下靜置2 h,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-苯甲醯胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物29)。(MS (m/z ) 478.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 9.02 (s, 1H), 8.46 - 7.88 (m, 6H), 7.88 - 7.01 (m, 4H), 6.09 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.62 (s, 3H)。To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.07 mmol) in pyridine (0.5 mL) was added benzyl chloride (0.07 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-(4-(5-benzamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 29). (MS ( m/z ) 478.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 9.02 (s, 1H), 8.46 - 7.88 (m, 6H), 7.88 - 7.01 (m, 4H), 6.09 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.62 (s, 3H).
化合物30-37(表1)類似地根據流程C,步驟4,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物5A)(實例21)遵循對於化合物29所描述之通用方法與表1中所列之試劑反應來製備。表 1 :根據流程 C ,步驟 4 製備之化合物。
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(中間物5A)(0.06 mmol)於吡啶(0.5 mL)中之混合物中添加1-Boc-吖呾-3-甲酸(0.067 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.064 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時將其在真空中濃縮且添加三氟乙酸(0.2 mL)。使反應混合物在磁性攪拌下靜置0.5 h,此時添加水(1 mL)及吡啶(0.5 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-(吖呾-3-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物38)。(MS (m/z ) 457.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.86 (s, 1H), 8.61 - 7.76 (m, 4H), 7.59 (d, J = 90.0 Hz, 1H), 6.07 (s, 1H), 4.53 - 4.18 (m, 4H), 4.00 (s, 3H), 3.87 (tt, J = 8.9, 7.1 Hz, 1H), 1.66 (d, J = 36.7 Hz, 3H)。 實例 54 :製備化合物 39 至 184 及 195 至 296 To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.06 mmol) in pyridine (0.5 mL) was added 1-Boc-aza-3-carboxylic acid (0.067 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.064 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 hours, at which time it was concentrated in vacuo and trifluoroacetic acid (0.2 mL) was added. The reaction mixture was allowed to stand with magnetic stirring for 0.5 h, at which time water (1 mL) and pyridine (0.5 mL) were added and the crude mixture was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(aza-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 38). (MS ( m/z ) 457.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.86 (s, 1H), 8.61 - 7.76 (m, 4H), 7.59 (d, J = 90.0 Hz, 1H), 6.07 (s, 1H), 4.53 - 4.18 (m, 4H), 4.00 (s, 3H), 3.87 (tt, J = 8.9, 7.1 Hz, 1H ), 1.66 (d, J = 36.7 Hz , 3H). Example 54 : Preparation of Compounds 39-184 and 195-296
化合物39至184及195至296一般根據流程C,步驟4合成。舉例而言,如下製備(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物39)。 Compounds 39-184 and 195-296 were generally synthesized according to Scheme C, step 4. For example, (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 39) was prepared as follows.
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(中間物5B)(0.06 mmol)於吡啶(0.5 mL)中之混合物中添加1-氰基環丙烷-1-甲酸(0.067 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.067 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物39)。(MS (m/z ) 469.1 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.79 (s, 1H), 8.33 - 7.46 (m, 4H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.82 - 1.36 (m, 7H)。To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5B) (0.06 mmol) in pyridine (0.5 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.067 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.067 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 39). (MS ( m/z ) 469.1 [M+H] + ). 1H NMR (400 MHz, Methanol- d4 ) δ 8.79 (s, 1H), 8.33 - 7.46 (m, 4H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.82 - 1.36 (m, 7H).
化合物40-160及195-206 (表2)類似地根據流程C,步驟4,遵循化合物39所描述之通用方法,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯,中間物5A(實例21)與表2中所列之試劑而非1-氰基環丙烷-1-甲酸反應來製備。 Compounds 40-160 and 195-206 (Table 2) were prepared similarly according to Scheme C, Step 4, following the general procedure described for compound 39 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester, Intermediate 5A (Example 21) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(中間物5B)(0.073 mmol)於吡啶(1.0 mL)中之混合物中添加2-(三氟甲基)嘧啶-5-甲酸(0.082 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.087 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(1-甲基-4-(5-(2-(三氟甲基)嘧啶-5-甲醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物251)。(MS (m/z ) 550.0 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 9.47 (s, 2H), 8.95 (s, 1H), 8.25 (dd, J = 8.6, 2.6 Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J = 8.7, 0.7 Hz, 1H), 7.87 (s, 1H), 5.95 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H)。To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5B) (0.073 mmol) in pyridine (1.0 mL) were added 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.082 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.087 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 251). (MS ( m/z ) 550.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 9.47 (s, 2H), 8.95 (s, 1H), 8.25 (dd, J = 8.6, 2.6 Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J = 8.7, 0.7 Hz, 1H), 7.87 (s, 1H), 5.95 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H).
化合物161-165及207-284 (表2)類似地根據流程C,步驟4,遵循化合物39所描述之通用方法,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯,中間物5B(實例22)與表2中所列之試劑而非1-氰基環丙烷-1-甲酸反應來製備。 Compounds 161-165 and 207-284 (Table 2) were prepared similarly according to Scheme C, Step 4, following the general method described for compound 39 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester, intermediate 5B (Example 22) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(中間物5B)(0.073 mmol)於吡啶(0.5 mL)中之混合物中添加3-氰基雙環[1.1.1]戊烷-1-甲酸(0.080 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.080 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-(3-氰基雙環[1.1.1]戊烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物162)。LCMS ((m/z ) 495.175 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 1H NMR (400 MHz, 甲醇-d4) δ 8.83 (s, 1H), 8.22 - 7.58 (m, 4H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H)。To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5B) (0.073 mmol) in pyridine (0.5 mL) were added 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid (0.080 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.080 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 162). LCMS (( m/z ) 495.175 [M+H] + ). 1H NMR (400 MHz, methanol-d 4 ) δ 1H NMR (400 MHz, methanol-d 4 ) δ 8.83 (s, 1H), 8.22 - 7.58 (m, 4H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H).
化合物166-168、285及288-290 (表2)類似地根據流程C,步驟4,遵循化合物39所描述之通用方法,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯,中間物5C(實例23)與表2中所列之試劑而非1-氰基環丙烷-1-甲酸反應來製備。 Compounds 166-168, 285 and 288-290 (Table 2) were prepared similarly according to Scheme C, Step 4, following the general procedure described for compound 39 by reacting (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, intermediate 5C (Example 23) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯鹽酸鹽(中間物5C)(0.070 mmol)於吡啶(1.0 mL)中之混合物中添加6-(三氟甲基)菸鹼酸(0.077 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.084 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(1-甲基-4-(5-(6-(三氟甲基)菸鹼醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(化合物288)。(MS (m/z ) 565.0 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 9.26 (d, J = 2.1 Hz, 1H), 8.97 (s, 1H), 8.64 - 8.52 (m, 1H), 8.34 - 8.15 (m, 2H), 8.11 - 7.68 (m, 3H), 6.03 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H), 1.60 (s, 3H)。 To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5C) (0.070 mmol) in pyridine (1.0 mL) were added 6-(trifluoromethyl)nicotinic acid (0.077 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.084 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 288). (MS ( m/z ) 565.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 9.26 (d, J = 2.1 Hz, 1H), 8.97 (s, 1H), 8.64 - 8.52 (m, 1H), 8.34 - 8.15 (m, 2H), 8.11 - 7.68 (m, 3H), 6.03 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H), 1.60 (s, 3H).
向(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯鹽酸鹽(中間物5C)(0.054 mmol)於吡啶(2.0 mL)中之混合物中添加1-(二氟甲基)環丙烷-1-甲酸(0.081 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.107 mmol)。使反應混合物以磁性攪拌2小時,濃縮且藉由HPLC純化,得到(R)-(4-(5-(1-(二氟甲基)環丙烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(化合物166)。(MS (m/z ) 510.15 [M+H]+ )。1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (bs, 1H), 9.63 (s, 1H), 8.73 (s, 1H), 8.42 (bs, 1H), 8.10 - 7.82 (m, 3H), 6.58 (t,J = 56.9 Hz, 1H), 5.83 (bs, 1H), 3.89 (s, 3H), 1.57 (bs, 3H), 1.43-1.27 (m, 2H), 1.24 - 1.03 (m, 2H)。To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5C) (0.054 mmol) in pyridine (2.0 mL) were added 1-(difluoromethyl)cyclopropane-1-carboxylic acid (0.081 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.107 mmol). The reaction mixture was stirred magnetically for 2 hours, concentrated and purified by HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 166). (MS ( m/z ) 510.15 [M+H] + ). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.86 (bs, 1H), 9.63 (s, 1H), 8.73 (s, 1H), 8.42 (bs, 1H), 8.10 - 7.82 (m, 3H), 6.58 (t, J = 56.9 Hz, 1H), 5.83 (bs, 1H), 3.89 (s, 3H), 1.57 (bs, 3H), 1.43-1.27 (m, 2H), 1.24 - 1.03 (m, 2H).
化合物169-174及290-296 (表2)類似地根據流程C,步驟4,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟吡啶-3-基)乙酯,中間物5D(實例24)與表2中所列之試劑替代1-氰基環丙烷-1-甲酸遵循化合物39所描述之通用方法反應來製備。Compounds 169-174 and 290-296 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester, intermediate 5D (Example 24) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.
化合物175-180 (表2)類似地根據流程C,步驟4,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(5-氟-2-甲基吡啶-3-基)乙酯,中間物5E(實例25)與表2中所列之試劑替代1-氰基環丙烷-1-甲酸遵循化合物39所描述之通用方法反應來製備。Compounds 175-180 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester, intermediate 5E (Example 25) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.
化合物181-182 (表2)類似地根據流程C,步驟4,藉由使(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-6-氟吡啶-3-基)乙酯,中間物5F(實例34)與表2中所列之試劑替代1-氰基環丙烷-1-甲酸遵循化合物39所描述之通用方法反應來製備。Compounds 181-182 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting 1-(2-chloro-6-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, intermediate 5F (Example 34) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.
化合物183-184 (表2)類似地根據流程C,步驟4,藉由使(R)-(4-(5-胺基-4-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯,中間物7B(實例18)與表2中所列之試劑替代1-氰基環丙烷-1-甲酸遵循化合物39所描述之通用方法反應來製備。Compounds 183-184 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester, intermediate 7B (Example 18) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.
化合物201-204、245-246及265-270(表2)使用表2中所列之試劑之外消旋混合物製備且藉由對掌性SFC純化來純化,得到單一立體異構體。表 2 :根據流程 C ,步驟 4 製備之化合物。
在0℃下向(R)-(4-(5-((1s,3S)-3-氰基-3-羥基環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物139)(0.04 mmol)之攪拌二氯甲烷(1 mL)溶液中添加三氟化硫(二乙胺基)(0.04 mmol)。將其緩慢升溫至室溫且攪拌12小時。用二氯甲烷稀釋混合物且用飽和碳酸鈉水溶液及鹽水洗滌。水層用二氯甲烷萃取,且合併之有機萃取物經(硫酸鈉)乾燥,過濾且在真空中濃縮,得到呈微黃色油狀物之標題化合物。殘餘物係藉由逆相HPLC純化以得到(R)-(4-(5-((1r,3R)-3-氰基-3-氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物185)。(MS (m/z ) 499.1 [M+H]+ )。1H NMR (400 MHz, 甲醇-d4) δ 8.92 (s, 1H), 8.32 (s, 1H), 8.21 - 7.78 (m, 3H), 7.39 (d, 1H), 6.21 - 5.92 (m, 1H), 5.01 - 4.65 (m, 2H), 4.00 (s, 3H), 2.76 (m, 1H), 1.94 - 1.79 (m, 2H), 1.55 (d, 3H)。 實例 56 : 製備 (R)-(4-(5-(1- 氰基 -3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 186) To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1s,3S)-3-cyano-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 139) (0.04 mmol) in stirred dichloromethane (1 mL) was added sulfur trifluoride (diethylamino) (0.04 mmol) at 0°C. It was slowly warmed to room temperature and stirred for 12 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution and brine. The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried over (sodium sulfate), filtered and concentrated in vacuo to give the title compound as a slightly yellow oil. The residue was purified by reverse phase HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((1r,3R)-3-cyano-3-fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 185). (MS ( m/z ) 499.1 [M+H] + ). 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.32 (s, 1H), 8.21 - 7.78 (m, 3H), 7.39 (d, 1H), 6.21 - 5.92 (m, 1H), 5.01 - 4.65 (m, 2H), 4.00 (s, 3H), 2.76 (m, 1H), 1.94 - 1.79 (m, 2H), 1.55 (d, 3H). Example 56 : Preparation of (R)-(4-(5-(1- cyano -3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 186)
在0℃下向(R)-(4-(5-(1-氰基-3-側氧基環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(20 mg,0.04 mmol)之攪拌二氯甲烷(1 mL)溶液中添加(二乙胺基)三氟化硫(30 mg,0.19 mmol)。將其緩慢升溫至室溫且攪拌12小時。用二氯甲烷稀釋混合物且用飽和碳酸鈉水溶液洗滌。將混合物在真空中濃縮。殘餘物係藉由逆相HPLC純化以得到(R)-(4-(5-(1-氰基-3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物186)。(MS (m/z ) 517.0 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 9.10 - 8.82 (m, 1H), 8.33 (s, 1H), 8.29 - 8.02 (m, 2H), 7.97 (d, 1H), 7.51 (s, 1H), 6.09 (d, 1H), 4.02 (d, 3H), 3.57 (m, 2H), 3.33 (m, 2H), 1.65 (s, 3H)。 實例 57 : 製備 (S)-(1- 甲基 -4-(5-(3- 甲基脲基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5-) 胺基甲酸 2- 氟 -1-(3- 氟苯基 ) 乙酯 ( 化合物 187) To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyano-3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (20 mg, 0.04 mmol) in stirred dichloromethane (1 mL) was added (diethylamino)sulfur trifluoride (30 mg, 0.19 mmol) at 0°C. It was slowly warmed to room temperature and stirred for 12 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC to give (R)-(4-(5-(1-cyano-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 186). (MS ( m/z ) 517.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 9.10 - 8.82 (m, 1H), 8.33 (s, 1H), 8.29 - 8.02 (m, 2H), 7.97 (d, 1H), 7.51 (s, 1H), 6.09 (d, 1H), 4.02 (d, 3H), 3.57 (m, 2H), 3.33 (m, 2H), 1.65 (s, 3H). Example 57 : Preparation of 2 - fluoro -1-(3-fluorophenyl ) ethyl (1- methyl -4-(5-(3- methylureido ) pyridin -2- yl )-1H-1,2,3 - triazole - 5- ) carbamate ( Compound 187)
將(S)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-(3-氟苯基)乙酯之鹽酸鹽(中間物6B)(0.05 mmol)溶解於二氯甲烷(1 mL)、吡啶(0.2 mL)中。添加三光氣(0.1 mmol),且在10分鐘之後添加2 M甲胺(0.5 mmol)於THF中之溶液。30 min後,反應物經濃縮且溶解於四氫呋喃(2 mL)及1 M氫氧化鈉水溶液(2 mL)中,且劇烈攪拌10分鐘。將反應物用飽和氯化銨淬滅,且用乙酸乙酯(2 × 10 mL)萃取。將合併之有機物經硫酸鈉乾燥,濃縮,且藉由逆相HPLC純化以得到(S)-(1-甲基-4-(5-(3-甲基脲基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸2-氟-1-(3-氟苯基)乙酯(化合物187)。(MS (m/z ) 432.2 [M+H]+ )。1 H NMR (400 MHz, 甲醇-d4 ) δ 8.81 (s, 1H), 8.02 (dd, J = 8.7, 2.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.61 - 6.59 (m, 4H), 6.14 - 5.62 (m, 1H), 4.78 - 4.39 (m, 2H), 3.98 (s, 3H), 2.80 (s, 3H)。 實例 58 :製備化合物 188 至 194 (S)-2-Fluoro-1-(3-fluorophenyl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 6B) (0.05 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Triphosgene (0.1 mmol) was added and after 10 minutes a solution of 2 M methylamine (0.5 mmol) in THF was added. After 30 min, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (S)-2-fluoro-1-(3-fluorophenyl)ethyl (1-methyl-4-(5-(3-methylureido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 187). (MS ( m/z ) 432.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.81 (s, 1H), 8.02 (dd, J = 8.7, 2.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.61 - 6.59 (m, 4H), 6.14 - 5.62 (m, 1H), 4.78 - 4.39 (m, 2H), 3.98 (s, 3H), 2.80 (s, 3H). Example 58 : Preparation of Compounds 188 to 194
化合物188至194一般根據流程C,步驟4合成。舉例而言,如下製備(R)-(4-(5-(吖呾-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物188)。 Compounds 188 to 194 were generally synthesized according to Scheme C, step 4. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(aza-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 188) was prepared as follows.
將(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(中間物5A)(實例21)(0.07 mmol)溶解於0.2 mL DCM及0.1 mL DMF中且用三乙基-胺(0.183 mmol)及氯甲酸苯酯(0.08 mmol)處理。攪拌反應物15 min且添加呈於THF中之溶液形式的吖呾(0.112 mmol)。15 min後,將反應物濃縮,隨後溶解於MeCN水溶液中且用TFA酸化。藉由RP-HPLC純化以得到呈TFA鹽形式之(R)-(4-(5-(吖呾-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物188)。(MS (m/z) 457.1 [M+H]+)。1H NMR (400 MHz, 乙腈-d3) δ 8.93 (s, 1H), 8.59 (bs, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.14 (ddd, J = 8.8, 2.6, 1.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 15.7 Hz, 2H), 6.04 (q, J = 6.6 Hz, 1H), 4.14 - 4.05 (m, 4H), 3.96 (s, 3H), 2.31 (dq, J = 8.2, 7.4 Hz, 2H), 1.59 (d, J = 6.6 Hz, 3H)。(R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A) (Example 21) (0.07 mmol) was dissolved in 0.2 mL DCM and 0.1 mL DMF and treated with triethyl-amine (0.183 mmol) and phenyl chloroformate (0.08 mmol). The reaction was stirred for 15 min and acrylamide (0.112 mmol) was added as a solution in THF. After 15 min, the reaction was concentrated, then dissolved in aqueous MeCN and acidified with TFA. Purification by RP-HPLC gave (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(aza-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 188) as a TFA salt (MS (m/z) 457.1 [M+H]+). 1H NMR (400 MHz, acetonitrile-d3) δ 8.93 (s, 1H), 8.59 (bs, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.14 (ddd, J = 8.8, 2.6, 1.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 15.7 Hz, 2H), 6.04 (q, J = 6.6 Hz, 1H), 4.14 - 4.05 (m, 4H), 3.96 (s, 3H), 2.31 (dq, J = 8.2, 7.4 Hz, 2H), 1.59 (d, J = 6.6 Hz, 3H).
化合物188-194(表3)類似地根據流程C,步驟4,遵循化合物188所描述之通用方法,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯,中間物5A(實例21)與表3中所列之試劑而非吖呾反應來製備。表 3 :根據流程 C ,步驟 4 製備之化合物。
化合物297至304一般根據流程C,步驟4合成,接著移除保護基。舉例而言,如下製備(R)-(4-(5-(3-氰基吖呾-3-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物297)。 步驟 1 : (R)-3- 氰基 -3-((6-(5-(((1-(2,5- 二氟吡啶 -3 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 吡啶 -3- 基 ) 胺甲醯基 ) 吖呾 -1- 甲酸三級丁酯 Compounds 297 to 304 were generally synthesized according to Scheme C, step 4, followed by removal of the protecting group. For example, (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanoazide-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 297) was prepared as follows. Step 1 : (R)-3- cyano -3-((6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) aminocarbonyl ) acryl -1- carboxylic acid tributyl ester
向小瓶中裝入(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(中間物5B)(0.12 mmol)、1-(三級丁氧基羰基)-3-氰基吖呾-3-甲酸(0.15 mmol)、N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.24 mmol)及吡啶(2 mL)。在室溫下攪拌反應混合物2小時,濃縮,用水稀釋且用EtOAc (3×)萃取。將合併之有機層用鹽水洗滌,經MgSO4 乾燥,過濾且濃縮,得到未經進一步純化即使用之(R)-3-氰基-3-((6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺甲醯基)吖呾-1-甲酸三級丁酯。(MS (m/z ) 584.3 [M+H]+ )。 步驟 2 : (R)-(4-(5-(3- 氰基 吖呾 -3- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 A vial was charged with (R)-ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 1-(2,5-difluoropyridin-3-yl) ester hydrochloride (Intermediate 5B) (0.12 mmol), 1-(tert-butyloxycarbonyl)-3-cyanoacridine-3-carboxylic acid (0.15 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature for 2 h, concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated to give (R)-3-cyano-3-((6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)aminocarbonyl)acryl-1-carboxylic acid tributyl ester which was used without further purification. (MS ( m/z ) 584.3 [M+H] + ). Step 2 : (R)-(4-(5-(3- cyanoacrylamide -3- carboxamido ) pyridin - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 - yl ) ethyl ester
在室溫下將(R)-3-氰基-3-((6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)胺甲醯基)吖呾-1-甲酸三級丁酯(0.12 mmol)於DCM (3 mL)及TFA (1 mL)中之溶液攪拌1小時。反應物經濃縮且藉由逆相HPLC純化以得到呈三氟乙酸鹽形式之(R)-(4-(5-(3-氰基吖呾-3-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z ) 484.0 [M+H]+ )。1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.85 (bs, 1H), 9.31 (bs, 2H), 8.69 (bs, 1H), 8.20 (bs, 1H), 8.11 - 7.83 (m, 3H), 5.80 (bs, 1H), 4.53 (q, J = 11.4 Hz, 4H), 3.90 (s, 3H), 1.41 (bs, 3H)。A solution of (R)-tributyl 3-cyano-3-((6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamyl)azetidine-1-carboxylate (0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 1 hour. The reaction was concentrated and purified by reverse phase HPLC to give 1-(2,5-difluoropyridin-3-yl)ethyl 3-cyano-3-((6-(5-((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamyl)azetidine-1-carboxylate as the trifluoroacetate salt. (MS ( m/z ) 484.0 [M+H] + ). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.85 (bs, 1H), 9.31 (bs, 2H), 8.69 (bs, 1H), 8.20 (bs, 1H), 8.11 - 7.83 (m, 3H), 5.80 (bs, 1H), 4.53 (q, J = 11.4 Hz, 4H), 3.90 (s, 3H), 1.41 (bs, 3H).
化合物298-303 (表4)類似地根據流程C,步驟4,藉由使(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(中間物5B)(實例22)與表4中所列之試劑而非1-(三級丁氧基羰基)-3-氰基吖呾-3-甲酸反應來製備。表 4 :根據流程 C ,步驟 4 製備之化合物。
向小瓶中裝入(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯鹽酸鹽(中間物5C)(0.19 mmol)、1-(((三級丁氧基羰基)胺基)甲基)-3,3-二氟環丁烷-1-甲酸(0.25 mmol)、N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.38 mmol)及吡啶(2 mL)。在室溫下攪拌反應混合物2小時,濃縮,用水稀釋且用EtOAc (3×)萃取。合併之有機層經鹽水洗滌,經MgSO4 乾燥,過濾且濃縮,得到未經進一步純化即使用之(R)-(4-(5-(1-(((三級丁氧基羰基)胺基)甲基)-3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯。(MS (m/z ) 639.1. [M+H]+ )。 步驟 2 : (R)-(4-(5-(1-( 胺甲基 )-3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 A vial was charged with (R)-ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 1-(2-chloro-5-fluoropyridin-3-yl) hydrochloride (Intermediate 5C) (0.19 mmol), 1-(((tert-butyloxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxylic acid (0.25 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature for 2 h, concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated to give 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (R)-(4-(5-(1-(((tributyloxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate which was used without further purification. (MS ( m/z ) 639.1. [M+H] + ). Step 2 : (R)-(4-(5-(1-( aminomethyl )-3,3 -difluorocyclobutane -1 -carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester
在室溫下將(R)-(4-(5-(1-(((三級丁氧基羰基)胺基)甲基)-3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(0.12 mmol)於DCM (3 mL)及TFA (1 mL)中之溶液攪拌18小時。反應物經濃縮且藉由逆相HPLC純化以得到呈三氟乙酸鹽形式之(R)-(4-(5-(1-(胺甲基)-3,3-二氟環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯。(MS (m/z ) 539.0 [M+H]+ )。1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.87 (bs, 1H), 8.76 (s, 1H), 8.44 (bs, 1H), 8.15 - 7.68 (m, 5H), 5.84 (bs, 1H), 3.90 (s, 3H), 3.51-3.22 (m, 2H), 3.21 (q, J = 13.3 Hz, 2H), 2.90 (q, J = 13.0 Hz, 2H), 1.57 (bs, 3H)。 實例 61 : 製備 (R)- (4-(5-(3- 氰基 -1-(2,2,2- 三氟乙基 ) 吖呾 -3- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 305) A solution of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-(((tributyloxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 18 h. The reaction was concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-(aminomethyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a trifluoroacetate salt (MS ( m/z ) 539.0 [M+H] + ). 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.87 (bs, 1H), 8.76 (s, 1H), 8.44 (bs, 1H), 8.15 - 7.68 (m, 5H), 5.84 (bs, 1H), 3.90 (s, 3H), 3.51-3.22 (m, 2H), 3.21 (q, J = 13.3 Hz, 2H), 2.90 (q, J = 13.0 Hz, 2H), 1.57 (bs, 3H). Example 61 : Preparation of (R)-1- (2,5-difluoropyridin-3-yl)ethyl (4-(5-(3-cyano-1- ( 2,2,2-trifluoroethyl) azetidine - 3 - carboxamido ) pyridin - 2 - yl )-1 - methyl -1H-1,2,3 - triazol - 5 - yl ) carbamate ( Compound 305 )
向小瓶中裝入呈三氟乙酸鹽(0.03 mmol)、三乙胺(0.15 mmol)及ACN (2 mL)形式之(R)-(4-(5-(3-氰基吖呾-3-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。添加2,2,2-三氟乙基三氟甲磺酸酯(0.09 mmol)且在60℃下加熱溶液2小時。反應物經濃縮且藉由逆相HPLC純化以得到(R)-(4-(5-(3-氰基-1-(2,2,2-三氟乙基)吖呾-3-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z ) 565.9 [M+H]+ )。1H NMR (400 MHz, DMSO-d6) δ 10.77 (bs, 1H), 9.84 (bs, 1H), 8.70 (bs, 1H), 8.19 (bs, 1H), 8.13-7.91 (m, 3H), 5.80 (bs, 1H), 3.96 (d, J = 7.6 Hz, 2H), 3.93-3.86 (m, 5H), 3.37 (q, J = 10.1 Hz, 2H), 1.58 (bs, 3H)。 實例 62 : 製備 (R)-(1- 甲基 -4-(5-((1r,3R)-3-((2,2,2- 三氟乙基 ) 胺基 ) 環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 306) 步驟 1 : (R)-(4-(5-((1r,3R)-3-(( 三級 丁氧基羰基 ) 胺基 ) 環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯。 A vial was charged with (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanoazide-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as trifluoroacetate (0.03 mmol), triethylamine (0.15 mmol), and ACN (2 mL). 2,2,2-Trifluoroethyl triflate (0.09 mmol) was added and the solution was heated at 60 °C for 2 h. The reaction was concentrated and purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyano-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS ( m/z ) 565.9 [M+H] + ). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (bs, 1H), 9.84 (bs, 1H), 8.70 (bs, 1H), 8.19 (bs, 1H), 8.13-7.91 (m, 3H), 5.80 (bs, 1H), 3.96 (d, J = 7.6 Hz, 2H), 3.93-3.86 (m, 5H), 3.37 (q, J = 10.1 Hz, 2H), 1.58 (bs, 3H). Example 62 : Preparation of (R)-(1- methyl -4-(5-((1r,3R)-3-((2,2,2- trifluoroethyl ) amino ) cyclobutane -1- carboxamido ) pyridin -2- yl )-1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 306) Step 1 : (R)-1-( 2-chloropyridin- 3-yl )ethyl(4-(5-((1r,3R)-3-(( tert -butyloxycarbonyl ) amino ) cyclobutane -1 - carboxamido ) pyridin -2 - yl ) -1 - methyl - 1H - 1,2,3 - triazol - 5 - yl ) carbamate .
將懸浮於二甲基甲醯胺(2 mL)中之(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(0.146 mmol)用(1r,3r)-3-((三級丁氧基羰基)胺基)環丁烷-1-甲酸(0.186 mmol)、1-乙基-3-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.438 mmol)及吡啶(0.869 mmol)處理。將反應混合物在室溫下攪拌30分鐘。濃縮反應混合物,得到粗產物。 步驟 2 : (R)-(4-(5-(1r,3R)-3- 胺基環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (0.146 mmol) suspended in dimethylformamide (2 mL) was treated with (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (0.186 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.438 mmol) and pyridine (0.869 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the crude product. Step 2 : (R)-(4-(5-(1r,3R)-3- aminocyclobutane -1 -carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester
溶解於二氯甲烷(2 mL)中之(R)-(4-(5-((1r,3R)-3-((三級丁氧基羰基)胺基)環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.105 mmol)用三氟乙酸(10.5 mmol)處理。在室溫下將反應混合物攪拌隔夜。濃縮反應混合物。將殘餘物再溶解於乙酸乙酯中且用飽和碳酸氫鈉溶液洗滌。分離各層。濃縮有機層,得到粗產物。 步驟 3 : (R)-(1- 甲基 -4-(5-((1r,3R)-3-((2,2,2- 三氟乙基 ) 胺基 ) 環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-((tributyloxycarbonyl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.105 mmol) dissolved in dichloromethane (2 mL) was treated with trifluoroacetic acid (10.5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The layers were separated. The organic layer was concentrated to give the crude product. Step 3 : (R)-1-(2-chloropyridin-3-yl)ethyl(1- methyl - 4-(5-((1r,3R)-3-((2,2,2-trifluoroethyl)amino)cyclobutane - 1 - carboxamido ) pyridin - 2 - yl ) -1H - 1,2,3 - triazol - 5 - yl ) carbamate
溶解於乙腈(4 mL)中之(R)-(4-(5-((1r,3R)-3-胺基環丁烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.0425 mmol)用三乙胺(0.215 mmol),接著用2,2,2-三氟乙基三氟甲磺酸酯處理(0.144 mmol)。反應混合物在室溫下攪拌隔夜且隨後濃縮。殘餘物係藉由HPLC純化,得到(R)-(1-甲基-4-(5-((1r,3R)-3-((2,2,2-三氟乙基)胺基)環丁烷-1-甲醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(MS (m/z) 553.1 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.86 (s, 1H), 8.39 - 8.24 (m, 2H), 8.09 (dd, J = 8.5, 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 7.7, 4.8 Hz, 1H), 6.07 (s, 1H), 4.16 (p, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.94 (t, J = 9.1 Hz, 1H), 2.74 (td, J = 8.6, 8.1, 4.1 Hz, 2H), 2.57 (dt, J = 13.6, 9.3 Hz, 2H), 1.55 (d, J = 46.0 Hz, 3H)。 實例 63 : 製備 (R)-(1- 甲基 -4-(5-((1s,3S)-3-((2,2,2- 三氟乙基 ) 胺基 ) 環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 307) (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-aminocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0425 mmol) dissolved in acetonitrile (4 mL) was treated with triethylamine (0.215 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.144 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-((1r,3R)-3-((2,2,2-trifluoroethyl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 553.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.39 - 8.24 (m, 2H), 8.09 (dd, J = 8.5, 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 7.7, 4.8 Hz, 1H), 6.07 (s, 1H), 4.16 (p, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.94 (t, J = 9.1 Hz, 1H), 2.74 (td, J = 8.6, 8.1, 4.1 Hz, 2H), 2.57 (dt, J = 13.6, 9.3 Hz, 2H), 1.55 (d, J = 46.0 Hz, 3H). Example 63 : Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1- methyl - 4- ( 5-((1s,3S)-3-((2,2,2- trifluoroethyl ) amino ) cyclobutane -1 - carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5 - yl ) carbamate ( Compound 307 )
標題化合物類似於實例62使用((1s,3s)-3-((三級丁氧基羰基)胺基)環丁烷-1-甲酸(0.186 mmol)代替(1r,3r)-3-((三級丁氧基羰基)胺基)環丁烷-1-甲酸來製備。(MS (m/z) 553 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.84 (s, 1H), 8.31 (s, 1H), 8.09 (dd, J = 8.7, 2.6 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.46 (s, 2H), 6.07 (s, 1H), 3.99 (s, 3H), 3.82 - 3.69 (m, 2H), 3.11 (d, J = 8.5 Hz, 2H), 2.74 - 2.60 (m, 2H), 2.43 (d, J = 10.6 Hz, 2H), 1.61 (s, 3H)。 實例 64 : 製備 (R)-(1- 甲基 -4-(5-((1R,5R,6r)-3-(2,2,2- 三氟乙基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 308) The title compound was prepared in analogy to Example 62 using ((1s,3s)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS (m/z) 553 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 1H), 8.31 (s, 1H), 8.09 (dd, J = 8.7, 2.6 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.46 (s, 2H), 6.07 (s, 1H), 3.99 (s, 3H), 3.82 - 3.69 (m, 3H), 3.11 (d, J = 8.5 Hz, 2H), 2.74 - 2.60 (m, 2H), 2.43 (d, J = 10.6 Hz, 2H), 1.61 (s, 3H). Example 64 : Preparation of (R)-(1- methyl -4-(5-((1R,5R,6r)-3-(2,2,2- trifluoroethyl )-3- azabicyclo [3.1.0] hexane -6- carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 308)
標題化合物類似於實例62使用胞外-3-((三級丁氧基)羰基]-3-氮雜雙環[3.1.0]己烷-6-甲酸(0.186 mmol)代替(1r,3r)-3-((三級丁氧基羰基)胺基)環丁烷-1-甲酸來製備。(MS (m/z) 565.1 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.95 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 7.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 6.09 (d, J = 6.9 Hz, 1H), 4.00 (s, 2H), 3.24 (dt, J = 19.5, 9.5 Hz, 4H), 2.87 - 2.76 (m, 2H), 2.21 (t, J = 2.9 Hz, 1H), 2.10 (t, J = 2.7 Hz, 2H), 1.63 (s, 3H)。 實例 65 : 製備 (R)-(1- 甲基 -4-(5-(1-(2,2,2- 三氟乙基 ) 吖呾 -3- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 309) The title compound was prepared similarly to Example 62 using exo-3-((tert-butyloxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS (m/z) 565.1 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 7.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 6.09 (d, J = 6.9 Hz, 1H), 4.00 (s, 2H), 3.24 (dt, J = 19.5, 9.5 Hz, 4H), 2.87 - 2.76 (m, 2H), 2.21 (t, J = 2.9 Hz, 1H), 2.10 (t, J = 2.7 Hz, 2H), 1.63 (s, 3H). Example 65 : Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (1- methyl - 4-(5-(1-(2,2,2- trifluoroethyl ) azabi -3 - carboxamido ) pyridin -2- yl ) -1H - 1,2,3 - triazol - 5 - yl ) carbamate ( Compound 309 )
標題化合物類似於實例62使用1-(三級丁氧基羰基)吖呾-3-甲酸(0.186 mmol)代替(1r,3r)-3-((三級丁氧基羰基)胺基)環丁烷-1-甲酸來製備。(MS (m/z) 539.1 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.90 (s, 1H), 8.33 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 4.43 (d, J = 7.8 Hz, 2H), 4.13 (d, J = 9.1 Hz, 2H), 4.00 (s, 2H), 3.86 (q, J = 8.0 Hz, 1H), 1.62 (s, 3H)。 實例 66 : 製備 (R)-(4-(5-(1- 胺基 -3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 310) 步驟 1 : (R)-(4-(5-(1-(( 三級丁氧基羰基 ) 胺基 )-3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 The title compound was prepared analogously to Example 62 using 1-(tert-butyloxycarbonyl)azetidine-3-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS (m/z) 539.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.33 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 4.43 (d, J = 7.8 Hz, 2H), 4.13 (d, J = 9.1 Hz, 2H), 4.00 (s, 2H), 3.86 (q, J = 8.0 Hz, 1H), 1.62 (s, 3H). Example 66 : Preparation of (R)-(4-(5-(1- amino -3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 310) Step 1 : (R)-(4-(5-(1-(( tributyloxycarbonyl ) amino )-3,3 -difluorocyclobutane -1 - carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester
在室溫下將(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(25 mg,0.061 mmol)、1-((三級丁氧基羰基)胺基)-3,3-二氟環丁烷-1-甲酸(31 mg,0.122 mmol)、EDCI (20 mg,0.1 mmol)於吡啶(1 ml)中之混合物攪拌1 h。藉由製備型HPLC用Gilson製備型HPLC (Gemini管柱,含30%-85% CH3 CN之H2 O及0.1% TFA)純化殘餘物,得到中間物。MS: 607.15 (M+1)。 步驟 2 : (R)-(4-(5-(1- 胺基 -3,3- 二氟環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5-) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯。 A mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (25 mg, 0.061 mmol), 1-((tert-butyloxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid (31 mg, 0.122 mmol), EDCI (20 mg, 0.1 mmol) in pyridine (1 ml) was stirred at room temperature for 1 h. The residue was purified by preparative HPLC using Gilson preparative HPLC (Gemini column, 30%-85% CH 3 CN in H 2 O and 0.1% TFA) to give an intermediate. MS: 607.15 (M+1). Step 2 : (R) -1-(2- chloropyridin - 3- yl ) ethyl(4-(5-(1- amino -3,3 -difluorocyclobutane -1 - carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5-) carbamate.
用2 mL含4 N HCl之二㗁烷處理以上中間物(20 mg)且在室溫下攪拌混合物隔夜。濃縮混合物。藉由製備型HPLC用Gilson製備型HPLC (Gemini管柱,含30%-85% CH3 CN之H2 O及0.1% TFA)純化殘餘物,得到產物。(MS (m/z) 507 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.89 (s, 1H), 8.32 (s, 1H), 8.15 (m, 1H), 7.95 (m, 1H), 7.68 - 7.25 (m, 2H), 6.08 (s, 1H), 4.00 (s, 3H), 3.72 (m, 2H), 3.19 (m, 2H), 1.86 - 1.40 (m, 3H)。實例 67 : 合成 (R)-(4-(5-(3-( 環丙胺基 ) 環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 311) 步驟 1. (R)-(1- 甲基 -4-(5-(3- 側氧基環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 The above intermediate (20 mg) was treated with 2 mL of 4 N HCl in dioxane and the mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by preparative HPLC using Gilson preparative HPLC (Gemini column, 30%-85% CH 3 CN in H 2 O and 0.1% TFA) to give the product. (MS (m/z) 507 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.32 (s, 1H), 8.15 (m, 1H), 7.95 (m, 1H), 7.68 - 7.25 (m, 2H), 6.08 (s, 1H), 4.00 (s, 3H), 3.72 (m, 2H), 3.19 (m, 2H), 1.86 - 1.40 (m, 3H). Example 67 : Synthesis of (R)-(4-(5-(3-( cyclopropylamino ) cyclobutane -1 - carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 311) Step 1. (R) -1-(2- chloropyridin -3- yl ) ethyl (1- methyl -4-(5-(3 -oxocyclobutane -1 -carboxamido ) pyridin - 2 -yl )-1H-1,2,3- triazol -5- yl ) carbamate
將懸浮於二甲基甲醯胺(2 mL)中之(R)-(4-(5-胺基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯鹽酸鹽(0.0975 mmol)用3-側氧基環丁烷-1-甲酸(0.131 mmol)、1-乙基-3-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.292 mmol)及吡啶(0.621 mmol)處理。在室溫下攪拌反應混合物30 min。將反應混合物用乙酸乙酯稀釋且用水洗滌。分離各層。濃縮有機層,得到粗(R)-(1-甲基-4-(5-(3-側氧基環丁烷-1-甲醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。 步驟 2. (R)-(1- 甲基 -4-(5-(3- 側氧基環丁烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (0.0975 mmol) suspended in dimethylformamide (2 mL) was treated with 3-oxocyclobutane-1-carboxylic acid (0.131 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.292 mmol) and pyridine (0.621 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and washed with water. The layers were separated. The organic layer was concentrated to give crude (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5- yl ) carbamate. Step 2. (R)-1-(2-chloropyridin-3-yl)ethyl (1 - methyl - 4-(5-(3 - oxocyclobutane -1 - carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5 - yl ) carbamate
將懸浮於二氯甲烷(1 mL)中之(R)-(1-甲基-4-(5-(3-側氧基環丁烷-1-甲醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.0638 mmol)用環丙胺(0.144 mmol)及三乙胺(0.215 mmol)處理。在室溫下攪拌10 min之後,添加三乙醯氧基硼氫化鈉(0.330 mmol)。將反應混合物在室溫下攪拌30分鐘。添加三氟乙酸(6.53 mmol)以淬滅反應物。隨後濃縮反應混合物且藉由HPLC純化,得到(R)-(1-甲基-4-(5-(3-側氧基環丁烷-1-甲醯胺基)吡啶-2-)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(MS (m/z) 511.2 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.88 (s, 1H), 8.32 (s, 1H), 8.20 - 8.00 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 6.08 (d, J = 7.1 Hz, 1H), 4.00 (s, 3H), 3.98 - 3.91 (m, 1H), 3.29 - 3.17 (m, 1H), 2.75 (ddt, J = 15.7, 12.1, 8.4 Hz, 3H), 2.65 - 2.48 (m, 2H), 1.78 - 1.37 (m, 3H), 0.95 (dtt, J = 7.4, 5.2, 2.8 Hz, 2H), 0.92 - 0.84 (m, 2H)。實例 68 : 合成 (R)-(4-(5-(3- 乙醯胺基雙環 [1.1.1] 戊烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 312) 步驟 1. (R)-(4-(5-(3-(( 三級丁氧基羰基 ) 胺基 ) 雙環 [1.1.1] 戊烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (0.0638 mmol) suspended in dichloromethane (1 mL) was treated with cyclopropylamine (0.144 mmol) and triethylamine (0.215 mmol). After stirring at room temperature for 10 min, sodium triacetoxyborohydride (0.330 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Trifluoroacetic acid (6.53 mmol) was added to quench the reaction. The reaction mixture was then concentrated and purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridine-2-)-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 511.2 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.32 (s, 1H), 8.20 - 8.00 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 6.08 (d, J = 7.1 Hz, 1H), 4.00 (s, 3H), 3.98 - 3.91 (m, 1H), 3.29 - 3.17 (m, 1H), 2.75 (ddt, J = 15.7, 12.1, 8.4 Hz, 3H), 2.65 - 2.48 (m, 2H), 1.78 - 1.37 (m, 3H), 0.95 (dtt, J = 7.4, 5.2, 2.8 Hz, 2H), 0.92 - 0.84 (m, 2H). Example 68 : Synthesis of (R)-(4-(5-(3- acetamidobicyclo [1.1.1] pentane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 312) Step 1. (R)-(4-(5-(3-(( tributyloxycarbonyl ) amino ) bicyclo [1.1.1] pentane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester
根據實例62之步驟1中所描述之步驟,使用3-((三級丁氧基羰基)胺基)雙環[1.1.1]戊烷-1-甲酸(0.186 mmol)代替(1r,3r)-3-((三級丁氧基羰基)胺基)環丁烷-1-甲酸來製備。 步驟 2. (R)-(4-(5-(3- 胺基雙環 [1.1.1] 戊烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 Prepared according to the procedure described in step 1 of Example 62, using 3-((tert-butyloxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. Step 2. 1-(2-chloropyridin-3-yl ) ethyl (R)-(4-(5-(3- aminobicyclo [1.1.1] pentane -1- carboxamido ) pyridin - 2 - yl )-1 - methyl - 1H -1,2,3- triazol - 5 - yl ) carbamate
根據實例62之步驟2中所描述之步驟製備。 步驟 3 .(R)-(4-(5-(3- 乙醯胺基雙環 [1.1.1] 戊烷 -1- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 Prepared according to the procedure described in step 2 of Example 62. Step 3. 1- (2-chloropyridin-3-yl ) ethyl (R)-(4-(5-(3- acetamidobicyclo [1.1.1] pentane -1 - carboxamido ) pyridin - 2 - yl )-1 - methyl - 1H -1,2,3 - triazol - 5 - yl ) carbamate
將溶解於乙腈中之(R)-(4-(5-(3-胺基雙環[1.1.1]戊烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.0425 mmol)用三乙胺(0.287 mmol)處理,接著用乙酸酐(0.212 mmol)處理。將反應混合物在室溫下攪拌20分鐘。濃縮反應混合物且藉由HPLC純化,得到雙醯化產物。將雙醯化產物溶解於四氫呋喃(2 mL)中且用1 N氫氧化鈉溶液(800 µL)處理。在室溫下攪拌反應混合物100 min。隨後濃縮反應混合物且藉由HPLC純化,得到(R)-(4-(5-(3-乙醯胺基雙環[1.1.1]戊烷-1-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(MS (m/z) 525.1 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.93 (s, 1H), 8.32 (s, 1H), 8.13 (dd, J = 8.6, 2.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.55 (s, 2H), 6.08 (d, J = 6.4 Hz, 1H), 3.99 (s, 3H), 2.44 (s, 6H), 1.94 (d, J = 8.8 Hz, 3H), 1.62 (s, 3H)。 實例 69 : 製備 (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 )-6- 甲基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 313) 步驟 1 : (R)-(6-(5-(((1-(2,5- 二氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-2- 甲基吡啶 -3- 基 ) 胺基甲酸三級丁酯 (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-aminobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0425 mmol) dissolved in acetonitrile was treated with triethylamine (0.287 mmol) followed by acetic anhydride (0.212 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated and purified by HPLC to give the bisacylated product. The bisacylated product was dissolved in tetrahydrofuran (2 mL) and treated with 1 N sodium hydroxide solution (800 µL). The reaction mixture was stirred at room temperature for 100 min. The reaction mixture was then concentrated and purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-(3-acetamidobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 525.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.32 (s, 1H), 8.13 (dd, J = 8.6, 2.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.55 (s, 2H), 6.08 (d, J = 6.4 Hz, 1H), 3.99 (s, 3H), 2.44 (s, 6H), 1.94 (d, J = 8.8 Hz, 3H), 1.62 (s, 3H). Example 69 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido )-6- methylpyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 313) Step 1 : (R)-(6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl )-2 -methylpyridin -3 -yl ) carbamic acid tributyl ester
將4-(5-((三級丁氧基羰基)胺基)-6-甲基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(3 mmol)、疊氮基三甲基矽烷(3 mmol)及T3P(50%於THF中)(4.5 mmol)溶解於THF(20 mL)中。在室溫下逐滴添加三乙胺(6 mmol),在5-30分鐘之後產生澄清溶液。添加(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇(4.5 mmol)且在80℃下加熱反應物2 h。隨後添加矽膠且在真空中濃縮粗混合物,且隨後藉由管柱層析純化,得到(R)-(6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-甲基吡啶-3-基)胺基甲酸三級丁酯(2.95 mmol)。 步驟 2 : (R)-(4-(5- 胺基 -6- 甲基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯氯化氫 4-(5-((tri-butyloxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (3 mmol), trimethylsilylazide (3 mmol) and T3P (50% in THF) (4.5 mmol) were dissolved in THF (20 mL). Triethylamine (6 mmol) was added dropwise at room temperature to give a clear solution after 5-30 min. (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (4.5 mmol) was added and the reaction was heated at 80 °C for 2 h. Silica gel was then added and the crude mixture was concentrated in vacuo and then purified by column chromatography to give (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl )carbamic acid tributyl ester (2.95 mmol). Step 2 : (R)-(4-(5- amino -6- methylpyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester hydrochloride
將(R)-(6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-甲基吡啶-3-基)胺基甲酸酯(2.95 mmol)懸浮於10 mL含4 M鹽酸之二㗁烷中1 h。隨後在真空中濃縮混合物,得到未經進一步純化即使用之(R)-(4-(5-胺基-6-甲基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯氯化氫。 步驟 3 : (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 )-6- 甲基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)carbamate (2.95 mmol) was suspended in 10 mL of 4 M hydrochloric acid in dioxane for 1 h. The mixture was then concentrated in vacuo to give (R)-(4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride which was used without further purification. Step 3 : (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido )-6- methylpyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin - 3 -yl ) ethyl ester
向(R)-(4-(5-胺基-6-甲基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯氯化氫(0.127 mmol)於吡啶(1 mL)中之混合物中添加1-氰基環丙烷-1-甲酸(0.254 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.139 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)-6-甲基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z) 483 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.17 - 7.66 (m, 4H), 5.95 (s, 1H), 3.99 (s, 3H), 2.46 (s, 3H), 1.82 - 1.39 (m, 7H)。 實例 70 : 製備 (R)-(1- 甲基 -4-(6- 甲基 -5-(2-( 三氟甲基 ) 嘧啶 -5- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 314) 步驟 1 : (R)-(1- 甲基 -4-(6- 甲基 -5-(2-( 三氟甲基 ) 嘧啶 -5- 甲醯胺基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.127 mmol) in pyridine (1 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.254 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.139 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 483 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.17 - 7.66 (m, 4H), 5.95 (s, 1H), 3.99 (s, 3H), 2.46 (s, 3H), 1.82 - 1.39 (m, 7H). Example 70 : Preparation of (R)-(1- methyl -4-(6- methyl -5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyridin -2- yl )-1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 314) Step 1 : (R)-(1- methyl -4-(6- methyl -5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester
向(R)-(4-(5-胺基-6-甲基吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(0.127 mmol)於吡啶(0.5 mL)中之混合物中添加2-(三氟甲基)嘧啶-5-甲酸(0.254 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.139 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(1-甲基-4-(6-甲基-5-(2-(三氟甲基)嘧啶-5-甲醯胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。LCMS (MS (m/z) 564 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.47 (s, 2H), 8.22 - 7.60 (m, 4H), 5.97 (s, 1H), 4.01 (s, 3H), 2.53 (s, 3H), 1.58 (d, J = 27.1 Hz, 3H)。 實例 71 : 製備 (R)-(4-(6- 氟 -5-(6-( 三氟甲基 ) 菸鹼醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 315) 步驟 1 : (R)-(4-(5- 胺基 -6- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 To a mixture of (R)-(4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (0.127 mmol) in pyridine (0.5 mL) were added 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.254 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.139 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(6-methyl-5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. LCMS (MS (m/z) 564 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.47 (s, 2H), 8.22 - 7.60 (m, 4H), 5.97 (s, 1H), 4.01 (s, 3H), 2.53 (s, 3H), 1.58 (d, J = 27.1 Hz, 3H). Example 71 : Preparation of (R)-(4-(6- fluoro -5-(6-( trifluoromethyl ) nicotinamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 315) Step 1 : (R)-(4-(5- amino -6- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester
在-78℃下,向(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(1.4 mmol)於四氫呋喃(15 mL)中之溶液中添加1 M雙(三甲基矽基)胺基鋰(1.4 mmol)之溶液。15分鐘後,添加2.5 M正丁基鋰(3.5 mmol)溶液。1小時後,添加2 M氯化鋅溶液(3.5 mmol),且在15℃下攪拌反應物30分鐘。此時,向反應物中添加6-溴-2-氟吡啶-3-胺(1.7 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(0.14 mmol)且將反應混合物加熱至80℃持續3小時。反應完成後,冷卻混合物且用飽和NaHCO3 淬滅,且用乙酸乙酯(30 mL,×2)萃取。將有機物分離,經硫酸鈉乾燥,且經由二氧化矽塞過濾,且不經進一步純化即用於下一步驟中。 步驟 2 : (R)-(4-(6- 氟 -5-(6-( 三氟甲基 ) 菸鹼醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.4 mmol) in tetrahydrofuran (15 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.4 mmol). After 15 min, a 2.5 M solution of n-butyllithium (3.5 mmol) was added. After 1 h, a 2 M solution of zinc chloride (3.5 mmol) was added and the reaction was stirred at 15 °C for 30 min. At this time, 6-bromo-2-fluoropyridin-3-amine (1.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.14 mmol) were added to the reaction and the reaction mixture was heated to 80 °C for 3 hours. After the reaction was complete, the mixture was cooled and quenched with saturated NaHCO3 and extracted with ethyl acetate (30 mL, x2). The organics were separated, dried over sodium sulfate, and filtered through a silica plug and used in the next step without further purification. Step 2 : (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6- fluoro - 5- ( 6- ( trifluoromethyl ) nicotinamido ) pyridin - 2- yl )-1- methyl -1H-1,2,3 - triazol -5 - yl ) carbamate
向(R)-(4-(5-胺基-6-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.15 mmol)於吡啶(1 mL)中之混合物中添加6-(三氟甲基)菸鹼酸(0.3 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.3 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(6-氟-5-(6-(三氟甲基)菸鹼醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物315)(MS (m/z) 565 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.31 - 9.13 (m, 1H), 8.67 - 8.43 (m, 2H), 8.43 - 8.06 (m, 2H), 8.07 - 7.80 (m, 2H), 7.49 (s, 1H), 6.12 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 1.55 (s, 3H)。 實例 72 : 製備 (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 )-6- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 316) To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 6-(trifluoromethyl)nicotinic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(6-fluoro-5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 315) (MS (m/z) 565 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.31 - 9.13 (m, 1H), 8.67 - 8.43 (m, 2H), 8.43 - 8.06 (m, 2H), 8.07 - 7.80 (m, 2H), 7.49 (s, 1H), 6.12 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 1.55 (s, 3H). Example 72 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1- carboxamido )-6- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 316)
向(R)-(4-(5-胺基-6-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.15 mmol)於吡啶(1 mL)中之混合物中添加1-氰基環丙烷-1-甲酸(0.3 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.3 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)-6-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(MS (m/z) 485 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.49 - 8.24 (m, 2H), 8.24 - 8.04 (m, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.68 - 7.26 (m, 1H), 6.11 (q, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.92 - 1.50 (m, 7H)。 實例 73 : 製備 (R)-(4-(4- 氟 -5-(6-( 三氟甲基 ) 菸鹼醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 317) 步驟 1 : (R)-(4-(5- 胺基 -4- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 485 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.49 - 8.24 (m, 2H), 8.24 - 8.04 (m, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.68 - 7.26 (m, 1H), 6.11 (q, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.92 - 1.50 (m, 7H). Example 73 : Preparation of (R)-(4-(4- fluoro -5-(6-( trifluoromethyl ) nicotinamidyl ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 317) Step 1 : (R)-(4-(5- amino -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester
在-78℃下,向(R)-(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(1.4 mmol)於四氫呋喃(15 mL)中之溶液中添加1 M雙(三甲基矽基)胺基鋰(1.4 mmol)之溶液。15分鐘後,添加2.5 M正丁基鋰(3.5 mmol)溶液。1小時後,添加2 M氯化鋅溶液(3.5 mmol),且在15℃下攪拌反應物30分鐘。此時,向反應物中添加6-溴-4-氟吡啶-3-胺(1.7 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(0.14 mmol)且將反應混合物加熱至80℃持續3小時。反應完成後,冷卻混合物且用飽和NaHCO3 淬滅,且用乙酸乙酯(30 mL,×2)萃取。將有機物分離,經硫酸鈉乾燥,且經由二氧化矽塞過濾,且不經進一步純化即用於下一步驟中。 步驟 2 : (R)-(4-(4- 氟 -5-(6-( 三氟甲基 ) 菸鹼醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.4 mmol) in tetrahydrofuran (15 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.4 mmol). After 15 min, a 2.5 M solution of n-butyllithium (3.5 mmol) was added. After 1 h, a 2 M solution of zinc chloride (3.5 mmol) was added and the reaction was stirred at 15 °C for 30 min. At this time, 6-bromo-4-fluoropyridin-3-amine (1.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.14 mmol) were added to the reaction and the reaction mixture was heated to 80 °C for 3 hours. After the reaction was complete, the mixture was cooled and quenched with saturated NaHCO3 and extracted with ethyl acetate (30 mL, x2). The organics were separated, dried over sodium sulfate, and filtered through a silica plug and used in the next step without further purification. Step 2 : (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4- fluoro - 5- ( 6- ( trifluoromethyl )nicotinamido ) pyridin - 2 - yl )-1- methyl -1H-1,2,3 - triazol -5 - yl ) carbamate
向(R)-(4-(5-胺基-6-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.15 mmol)於吡啶(1 mL)中之混合物中添加6-(三氟甲基)菸鹼酸(0.3 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.3 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(4-氟-5-(6-(三氟甲基)菸鹼醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯。(MS (m/z) 564.9 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.38 - 9.20 (m, 1H), 8.60 (d, J = 8.1 Hz, 1H), 8.35 - 8.26 (m, 1H), 8.07 - 7.93 (m, 2H), 7.88 (d, J = 11.3 Hz, 1H), 7.63 - 7.34 (m, 2H), 6.16 - 6.03 (m, 1H), 4.01 (s, 3H), 1.55 (s, 3H)。 實例 74 : 製備 (R)-(4-(6- 氟 -5-(2-( 三氟甲基 ) 嘧啶 -5- 甲醯胺基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 318) To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 6-(trifluoromethyl)nicotinic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-fluoro-5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 564.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.38 - 9.20 (m, 1H), 8.60 (d, J = 8.1 Hz, 1H), 8.35 - 8.26 (m, 1H), 8.07 - 7.93 (m, 2H), 7.88 (d, J = 11.3 Hz, 1H), 7.63 - 7.34 (m, 2H), 6.16 - 6.03 (m, 1H), 4.01 (s, 3H), 1.55 (s, 3H). Example 74 : Preparation of (R)-(4-(6- fluoro -5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 318)
向(R)-(4-(5-胺基-6-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(0.15 mmol)於吡啶(1 mL)中之混合物中添加2-(三氟甲基)嘧啶-5-甲酸(0.3 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.3 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(6-氟-5-(2-(三氟甲基)嘧啶-5-甲醯胺基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(MS(m/z)566[M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.46 (s, 2H), 8.57 (dd, J = 9.8, 8.2 Hz, 1H), 8.45 - 8.02 (m, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 6.12 (q, J = 6.5 Hz, 1H), 4.00 (s, 3H), 1.66 (s, 3H)。 實例 75 : 製備 (R)-(4-(5-(6- 氯煙醯胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 319) 步驟 1 : (2- 溴嘧啶 -5- 基 ) 胺基甲酸三級丁酯 To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(6-fluoro-5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (MS (m/z) 566 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.46 (s, 2H), 8.57 (dd, J = 9.8, 8.2 Hz, 1H), 8.45 - 8.02 (m, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 6.12 (q, J = 6.5 Hz, 1H), 4.00 (s, 3H), 1.66 (s, 3H). Example 75 : Preparation of (R)-(4-(5-(6- chloronitroamino ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 319) Step 1 : (2- bromopyrimidin -5- yl ) carbamic acid tert-butyl ester
向2-溴嘧啶-5-胺(23 mmol)於THF(28 mL)中之溶液中添加二-二碳酸三級丁酯(34.4 mmol)。將反應物加熱至70℃持續16 h,隨後添加二-二碳酸三級丁酯(18.3 mmol)。隨後在70℃下攪拌反應物2 h。濃縮反應混合物以得到(2-溴嘧啶-5-基)胺基甲酸三級丁酯。 步驟 2 : 4-(5-(( 三級丁氧基羰基 ) 胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 ( 中間物 9) To a solution of 2-bromopyrimidin-5-amine (23 mmol) in THF (28 mL) was added tert-butyl dicarbonate (34.4 mmol). The reaction was heated to 70 °C for 16 h, followed by the addition of tert-butyl dicarbonate (18.3 mmol). The reaction was then stirred at 70 °C for 2 h. The reaction mixture was concentrated to give tert-butyl (2-bromopyrimidin-5-yl)carbamate. Step 2 : 4-(5-(( tert-butyloxycarbonyl ) amino ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid ( Intermediate 9)
在−70℃下向4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(48.5 mmol)於四氫呋喃(500 mL)中之溶液中添加1 M雙(三甲基矽基)胺基鋰(53.4 mmol)溶液。15分鐘後,添加2.5 M正丁基鋰(101.8 mmol)溶液。1小時後,添加2 M氯化鋅溶液(101.9 mmol),且在15℃下攪拌反應物30分鐘。此時,向反應物中添加(2-溴嘧啶-5-基)胺基甲酸三級丁酯(29.1 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(4.85 mmol)且將反應混合物加熱至90℃持續16 h。反應完成後,冷卻混合物且添加2 M氫氧化鈉水溶液(800 mL)。分離有機物,且用甲基三級丁基醚(500 mL×2)萃取水層。丟棄有機物,且水層用12 M HCl (140 mL)及石油醚(160 mL)處理。粉碎產物且過濾且經30:1甲基三級丁基醚/二氯甲烷(70 mL)洗滌,隨後藉由管柱層析純化,得到4-(5-((三級丁氧基羰基)胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物9)。 步驟 3 : (R)-(2-(5-(((1-(2,5- 二氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 嘧啶 -5- 基 ) 胺基甲酸三級丁酯 To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (48.5 mmol) in tetrahydrofuran (500 mL) at −70 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (53.4 mmol). After 15 minutes, a 2.5 M solution of n-butyl lithium (101.8 mmol) was added. After 1 hour, a 2 M solution of zinc chloride (101.9 mmol) was added and the reaction was stirred at 15 °C for 30 minutes. At this point, tributyl (2-bromopyrimidin-5-yl)carbamate (29.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.85 mmol) were added to the reaction and the reaction mixture was heated to 90 °C for 16 h. After the reaction was completed, the mixture was cooled and 2 M aqueous sodium hydroxide solution (800 mL) was added. The organics were separated and the aqueous layer was extracted with methyl tert-butyl ether (500 mL×2). The organics were discarded and the aqueous layer was treated with 12 M HCl (140 mL) and petroleum ether (160 mL). The product was crushed and filtered and washed with 30:1 methyl tert-butyl ether/dichloromethane (70 mL), followed by purification by column chromatography to give 4-(5-((tert-butyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 9). Step 3 : (R)-(2-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyrimidin -5- yl ) carbamic acid tributyl ester
將4-(5-((三級丁氧基羰基)胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物9)(0.97 mmol)、疊氮基三甲基矽烷(1.46 mmol)及T3P(50%於DMF中)(1.46 mmol)溶解於THF(5 mL)中。在室溫下逐滴添加三乙胺(1.95 mmol)。將反應物加熱至70℃持續50分鐘,隨後添加(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇(1.45 mmol),且在70℃下再加熱反應物6小時。反應物經濃縮且隨後藉由管柱層析純化以得到(R)-(2-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)嘧啶-5-基)胺基甲酸三級丁酯。 步驟 4 : (R)-(4-(5- 胺基嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 4-(5-((tri-butyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 9) (0.97 mmol), trimethylsilyl azide (1.46 mmol) and T3P (50% in DMF) (1.46 mmol) were dissolved in THF (5 mL). Triethylamine (1.95 mmol) was added dropwise at room temperature. The reaction was heated to 70 °C for 50 min, then (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (1.45 mmol) was added and the reaction was heated at 70 °C for another 6 h. The reactants were concentrated and then purified by column chromatography to obtain (R)-(2-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)carbamic acid tert-butyl ester. Step 4 : (R)-(4-(5- aminopyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester
向(R)-(2-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)嘧啶-5-基)胺基甲酸三級丁酯(0.52 mmol)於二氯甲烷(3.4 mL)中之溶液中添加含4 M HCl之1,4-二㗁烷(3.8 mL)之溶液。在室溫下攪拌反應物2 h。濃縮反應物,得到呈鹽酸鹽形式之(R)-(4-(5-胺基嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。 步驟 5 : (R)-(4-(5-(6- 氯煙醯胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 To a solution of (R)-tributyl(2-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)carbamate (0.52 mmol) in dichloromethane (3.4 mL) was added a solution of 4 M HCl in 1,4-dioxane (3.8 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated to give 1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as the hydrochloride salt. Step 5 : (R)-(4-(5-(6- chloronicotinamide ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester
向(R)-(4-(5-胺基嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(0.073 mmol)於吡啶(1 mL)中之混合物中添加6-氯菸鹼酸(0.082 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.087 mmol)。攪拌反應混合物1小時,隨後濃縮。將殘餘物溶解於乙腈及水(2 mL)中,且藉由HPLC純化以得到(R)-(4-(5-(6-氯煙醯胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物319)。(MS (m/z) 516.0 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.19 (s, 2H), 8.98 (d, J = 2.5 Hz, 1H), 8.37 (dd, J = 8.3, 2.5 Hz, 1H), 8.04 (s, 1H), 7.71 - 7.59 (m, 2H), 5.96 (d, J = 6.2 Hz, 1H), 4.01 (s, 3H), 1.61 (s, 3H)。 實例 76 : 製備 (R)-(4-(5-(6- 氯煙醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 320) 步驟 1 : (5- 溴吡 𠯤 -2- 基 ) 胺基甲酸三級丁酯 To a mixture of (R)-(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (0.073 mmol) in pyridine (1 mL) was added 6-chloronicotinic acid (0.082 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.087 mmol). The reaction mixture was stirred for 1 hour and then concentrated. The residue was dissolved in acetonitrile and water (2 mL) and purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(6-chloronicotinoyl)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 319). (MS (m/z) 516.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.19 (s, 2H), 8.98 (d, J = 2.5 Hz, 1H), 8.37 (dd, J = 8.3, 2.5 Hz, 1H), 8.04 (s, 1H), 7.71 - 7.59 (m, 2H), 5.96 (d, J = 6.2 Hz, 1H), 4.01 (s, 3H), 1.61 (s, 3H). Example 76 : Preparation of (R)-(4-(5-(6- chloronitroamino ) pyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 320) Step 1 : (5- bromopyridine - 2- yl ) carbamic acid tributyl ester
在0℃下向5-溴吡𠯤-2-胺(689 mmol)於DCM(840 mL)中之溶液中添加二異丙基乙胺(2.07 mol)、DMAP(689 mmol)及二-二碳酸三級丁酯(34.4 mmol)。在室溫下攪拌反應物16小時。濃縮反應混合物,隨後藉由管柱層析純化,得到(5-溴吡𠯤-2-基)胺基甲酸三級丁酯。 步驟 2 : 4-(5-(( 三級丁氧基羰基 ) 胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 To a solution of 5-bromopyridine-2-amine (689 mmol) in DCM (840 mL) was added diisopropylethylamine (2.07 mol), DMAP (689 mmol) and tert-butyl dicarbonate (34.4 mmol) at 0°C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated and then purified by column chromatography to give tert-butyl (5-bromopyridine-2-yl)carbamate. Step 2 : 4-(5-(( tert-butyloxycarbonyl ) amino ) pyridine - 2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid
在−70℃下向4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(242 mmol)於四氫呋喃(2.5 L)中之溶液中添加1 M雙(三甲基矽基)胺基鋰(266 mmol)溶液。15分鐘後,添加2.5 M正丁基鋰(507.5 mmol)溶液。1小時後,添加2 M氯化鋅溶液(509.7 mmol),且在15℃下攪拌反應物30分鐘。此時,向反應物中添加(5-溴吡𠯤-2-基)胺基甲酸三級丁酯(218 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(24.2 mmol)且將反應混合物加熱至90℃持續16 h。反應完成後,冷卻混合物且添加2 M氫氧化鈉水溶液(1.5 L)。分離有機物,且用甲基三級丁基醚(2.0 L×2)萃取水層。丟棄有機物,且水層用12 M HCl (250 mL)及甲基三級丁基醚(900 mL)處理。將產物析出且過濾並用甲基三級丁基醚(300 mL)洗滌,得到4-(5-((三級丁氧基羰基)胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸。 步驟 3 : (R)-(5-(5-(((1-(2,5- 二氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 吡 𠯤 -2- 基 ) 胺基甲酸三級丁酯 To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (242 mmol) in tetrahydrofuran (2.5 L) at −70 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (266 mmol). After 15 min, a 2.5 M solution of n-butyl lithium (507.5 mmol) was added. After 1 h, a 2 M solution of zinc chloride (509.7 mmol) was added and the reaction was stirred at 15 °C for 30 min. At this point, tributyl (5-bromopyridin-2-yl)carbamate (218 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24.2 mmol) were added to the reaction and the reaction mixture was heated to 90 °C for 16 h. After the reaction was complete, the mixture was cooled and 2 M aqueous sodium hydroxide solution (1.5 L) was added. The organics were separated and the aqueous layer was extracted with methyl tert-butyl ether (2.0 L×2). The organics were discarded and the aqueous layer was treated with 12 M HCl (250 mL) and methyl tert-butyl ether (900 mL). The product was precipitated and filtered and washed with methyl tert-butyl ether (300 mL) to give 4-(5-((tert-butyloxycarbonyl)amino)pyrrolidine-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 3 : (R)-(5-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyrrol - 2- yl ) carbamic acid tributyl ester
將4-(5-((三級丁氧基羰基)胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(0.62 mmol)、疊氮基三甲基矽烷(0.94 mmol)及T3P(50%於DMF中)(0.94 mmol)溶解於THF(5 mL)中。在室溫下逐滴添加三乙胺(1.25 mmol),接著添加(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇(0.93 mmol)。在70℃下加熱反應物6小時。反應物經濃縮且隨後藉由管柱層析純化以得到(R)-(5-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡𠯤-2-基)胺基甲酸三級丁酯。 步驟 4 : (R)-(4-(5- 胺基吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 中間物 10) 4-(5-((tri-butyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.62 mmol), trimethylsilyl azide (0.94 mmol) and T3P (50% in DMF) (0.94 mmol) were dissolved in THF (5 mL). Triethylamine (1.25 mmol) was added dropwise at room temperature followed by (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (0.93 mmol). The reaction was heated at 70 °C for 6 h. The reactants were concentrated and then purified by column chromatography to give (R)-(5-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl) pyrrolidone )carbamate tert - butyl ester. Step 4 : (R)-(4-(5- aminopyrrolidone )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate 1- (2,5 -difluoropyridin -3 -yl ) ethyl ester ( Intermediate 10)
向(R)-(5-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)吡𠯤-2-基)胺基甲酸三級丁酯(0.52 mmol)於二氯甲烷(3.4 mL)中之溶液中添加4M含HCl之1,4-二㗁烷溶液(3.8 mL)。在室溫下攪拌反應物2 h。濃縮反應物,得到呈鹽酸鹽形式之(R)-(4-(5-胺基吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(中間物10)。 步驟 5 : (R)-(4-(5-(6- 氯煙醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 To a solution of (R)-tributyl(5-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyrrol-2-yl)carbamate (0.52 mmol) in dichloromethane (3.4 mL) was added 4M HCl in 1,4-dioxane (3.8 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated to give 1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyrrol-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as the hydrochloride salt (Intermediate 10). Step 5 : (R)-(4-(5-(6- chloronicotinamide ) pyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester
向(R)-(4-(5-胺基吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(中間物10)(0.073 mmol)於吡啶(1 mL)中之混合物中添加6-氯菸鹼酸(0.082 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.087 mmol)。攪拌反應混合物1 h,隨後濃縮。將殘餘物溶解於乙腈及水(2 mL)中,且藉由HPLC純化以得到(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物320)。(MS (m/z) 515.9 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.44 (s, 1H), 9.01 - 8.90 (m, 2H), 8.38 (dd, J = 8.4, 2.5 Hz, 1H), 8.09 - 7.98 (m, 2H), 7.64 (dd, J = 8.3, 0.7 Hz, 1H), 5.95 (d, J = 7.0 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H)。 實例 77 : 製備 (R)-(4-(5-(6-( 二氟甲基 ) 菸鹼醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 321) To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 10) (0.073 mmol) in pyridine (1 mL) was added 6-chloronicotinic acid (0.082 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.087 mmol). The reaction mixture was stirred for 1 h and then concentrated. The residue was dissolved in acetonitrile and water (2 mL) and purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(6-chloronicotinoyl)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 320). (MS (m/z) 515.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.44 (s, 1H), 9.01 - 8.90 (m, 2H), 8.38 (dd, J = 8.4, 2.5 Hz, 1H), 8.09 - 7.98 (m, 2H), 7.64 (dd, J = 8.3, 0.7 Hz, 1H), 5.95 (d, J = 7.0 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Example 77 : Preparation of (R)-(4-(5-(6-( difluoromethyl ) nicotinoyl ) pyrrolidone -2 - yl ) -1- methyl - 1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 - yl ) ethyl ester ( Compound 321)
遵循實例76中所描述之關於使用6-(二氟甲基)菸鹼酸(0.08 mmol)代替6-氯菸鹼酸製備(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯的步驟,得到(R)-(4-(5-(6-(二氟甲基)菸鹼醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物321)。(MS (m/z) 532.0 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.46 (d, J = 1.5 Hz, 1H), 9.29 - 9.16 (m, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.55 (dd, J = 8.2, 2.2 Hz, 1H), 8.05 (s, 1H), 7.93 - 7.78 (m, 2H), 6.83 (t, J = 55.0 Hz, 1H), 5.95 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H)。 實例 78 : 製備 (R)-(1- 甲基 -4-(5-(6-( 三氟甲基 ) 菸鹼醯胺基 ) 吡 𠯤 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 322) The procedure described in Example 76 for the preparation of (R)-(4-(5-(6-chloronicotinamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester was followed using 6-(difluoromethyl)nicotinic acid (0.08 mmol) instead of 6-chloronicotinic acid to give (R)-(4-(5-(6-(difluoromethyl)nicotinamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester (Compound 321). (MS (m/z) 532.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.46 (d, J = 1.5 Hz, 1H), 9.29 - 9.16 (m, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.55 (dd, J = 8.2, 2.2 Hz, 1H), 8.05 (s, 1H), 7.93 - 7.78 (m, 2H), 6.83 (t, J = 55.0 Hz, 1H), 5.95 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Example 78 : Preparation of (R)-(1- methyl -4-(5-(6-( trifluoromethyl ) nicotinamido ) pyrrolidone - 2- yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 - yl ) ethyl ester ( Compound 322)
遵循實例76中所描述之關於使用6-(三氟甲基)菸鹼酸(0.08 mmol)代替6-氯菸鹼酸製備(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯的步驟,得到(R)-(1-甲基-4-(5-(6-(三氟甲基)菸鹼醯胺基)吡𠯤-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物322)。(MS (m/z) 549.9 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.49 (d, J = 20.4 Hz, 1H), 9.27 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.70 - 8.50 (m, 1H), 8.11 - 7.70 (m, 3H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.63 (s, 3H)。 實例 79 : 製備 (R)-(4-(5-(2,3- 二氟異煙醯胺吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 323) The procedure described in Example 76 for the preparation of (R)-(4-(5-(6-chloronicotinamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester was followed using 6-(trifluoromethyl)nicotinic acid (0.08 mmol) instead of 6-chloronicotinic acid to give (R)-(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyrrolidone-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester (Compound 322). (MS (m/z) 549.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.49 (d, J = 20.4 Hz, 1H), 9.27 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.70 - 8.50 (m, 1H), 8.11 - 7.70 (m, 3H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.63 (s, 3H). Example 79 : Preparation of (R)-(4-(5-(2,3 -difluoroisocyanatopyridin - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 323)
遵循實例76中所描述之關於使用2,3-二氟異煙酸(0.08 mmol)代替6-氯菸鹼酸製備(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯的步驟,得到(R)-(4-(5-(2,3-二氟異煙醯胺)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物323)。(MS (m/z) 518.0 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.41 (s, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.14 (dd, J = 5.1, 1.4 Hz, 1H), 8.05 (s, 1H), 8.00 - 7.72 (m, 1H), 7.62 (dd, J = 5.0, 4.0 Hz, 1H), 5.95 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H)。 實例 80 : 製備 (R)-(4-(5-(2-( 二氟甲基 ) 嘧啶 -5- 甲醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯吡啶 -3- 基 ) 乙酯 ( 化合物 324) The procedure described in Example 76 for the preparation of (R)-(4-(5-(6-chloronicotinamide)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester was followed using 2,3-difluoroisonicotinic acid (0.08 mmol) instead of 6-chloronicotinic acid to give (R)-(4-(5-(2,3-difluoroisonicotinamide)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester (Compound 323). (MS (m/z) 518.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.41 (s, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.14 (dd, J = 5.1, 1.4 Hz, 1H), 8.05 (s, 1H), 8.00 - 7.72 (m, 1H), 7.62 (dd, J = 5.0, 4.0 Hz, 1H), 5.95 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Example 80 : Preparation of (R)-(4-(5-(2-( difluoromethyl ) pyrimidine -5- carboxamido ) pyrrolidone -2- yl )-1- methyl - 1H -1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 324)
遵循實例76中所描述之關於在步驟3中使用(R)-1-(2-氯吡啶-3-基)乙-1-醇(4.64 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,且在步驟5中使用2-(二氟甲基)嘧啶-5-甲酸(0.08 mmol)代替6-氯菸鹼酸製備(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯的步驟,得到(R)-(4-(5-(2-(二氟甲基)嘧啶-5-甲醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯吡啶-3-基)乙酯(化合物324)。(MS (m/z) 531.0 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.56 - 9.27 (m, 3H), 8.96 (s, 1H), 8.43 - 7.85 (m, 2H), 7.52 (s, 1H), 6.84 (t, J = 54.2 Hz, 1H), 6.07 (t, J = 6.5 Hz, 1H), 4.00 (s, 3H), 1.61 (s, 3H)。 實例 81 : 製備 (R)-(1- 甲基 -4-(5-(2-( 三氟甲基 ) 嘧啶 -5- 甲醯胺基 ) 吡 𠯤 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 325) The procedure described in Example 76 was followed using (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 2-(difluoromethyl)pyrimidine-5-carboxylic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 1-(2-(difluoromethyl)pyrimidine-5-carboxamido)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 324) was obtained. (MS (m/z) 531.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.56 - 9.27 (m, 3H), 8.96 (s, 1H), 8.43 - 7.85 (m, 2H), 7.52 (s, 1H), 6.84 (t, J = 54.2 Hz, 1H), 6.07 (t, J = 6.5 Hz, 1H), 4.00 (s, 3H), 1.61 (s, 3H). Example 81 : Preparation of (R)-(1- methyl -4-(5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyrrolidone -2- yl )-1H-1,2,3- triazol - 5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Compound 325)
遵循實例76中所描述之關於在步驟3中使用(R)-1-(2-氟吡啶-3-基)乙-1-醇(4.64 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,且在步驟5中使用2-(三氟甲基)嘧啶-5-甲酸(0.08 mmol)代替6-氯菸鹼酸製備(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯的步驟,得到(R)-(1-甲基-4-(5-(2-(三氟甲基)嘧啶-5-甲醯胺基)吡𠯤-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟吡啶-3-基)乙酯(化合物325)。(MS (m/z) 532.9 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.49 (s, 2H), 9.45 (s, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.23 - 7.85 (m, 2H), 7.41 (s, 1H), 5.99 (q, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H)。 實例 82 : 製備 (R)-(1- 甲基 -4-(5-(6-( 三氟甲基 ) 菸鹼醯胺基 ) 吡 𠯤 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 326) The procedure described in Example 76 was followed using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 2-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 325) was obtained. (MS (m/z) 532.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.49 (s, 2H), 9.45 (s, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.23 - 7.85 (m, 2H), 7.41 (s, 1H), 5.99 (q, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H). Example 82 : Preparation of (R)-(1- methyl -4-(5-(6-( trifluoromethyl ) nicotinoyl ) pyrrolidone - 2 -yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Compound 326)
遵循實例76中所描述之關於在步驟3中使用(R)-1-(2-氟吡啶-3-基)乙-1-醇(4.64 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,且在步驟5中使用6-(三氟甲基)菸鹼酸(0.08 mmol)代替6-氯菸鹼酸製備(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯的步驟,得到(R)-(1-甲基-4-(5-(6-(三氟甲基)菸鹼醯胺基)吡𠯤-2-基)-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟吡啶-3-基)乙酯(化合物326)。(MS (m/z) 532.0 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.47 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.60 (dd, J = 8.3, 2.1 Hz, 1H), 8.25 - 8.06 (m, 2H), 8.01 (dd, J = 8.2, 0.8 Hz, 1H), 7.41 (s, 1H), 5.99 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H)。 實例 83 : 製備 (R)-(4-(5-(2-( 二氟甲基 ) 嘧啶 -5- 甲醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 327) The procedure described in Example 76 was followed with the use of (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 6-(trifluoromethyl)nicotinic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidone)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 2-(4-(5-(6-(trifluoromethyl)nicotinoyl)pyrrolidone)-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 326) was obtained. (MS (m/z) 532.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.47 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.60 (dd, J = 8.3, 2.1 Hz, 1H), 8.25 - 8.06 (m, 2H), 8.01 (dd, J = 8.2, 0.8 Hz, 1H), 7.41 (s, 1H), 5.99 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H). Example 83 : Preparation of (R)-(4-(5-(2-( difluoromethyl ) pyrimidine -5- carboxamido ) pyrrolidone -2- yl )-1- methyl - 1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Compound 327)
遵循實例76中所描述之關於在步驟3中使用(R)-1-(2-氟吡啶-3-基)乙-1-醇(4.64 mmol)代替(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇,且在步驟5中使用2-(二氟甲基)嘧啶-5-甲酸(0.08 mmol)代替6-氯菸鹼酸製備(R)-(4-(5-(6-氯煙醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯的步驟,得到(R)-(4-(5-(2-(二氟甲基)嘧啶-5-甲醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氟吡啶-3-基)乙酯(化合物327)。(MS (m/z) 514.9 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.62 - 9.34 (m, 3H), 8.97 (s, 1H), 8.30 - 7.93 (m, 2H), 7.41 (s, 1H), 6.84 (t, J = 54.1 Hz, 1H), 5.99 (d, J = 7.2 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H)。 實例 84 : 製備 (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 328) The procedure described in Example 76 was followed using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 2-(difluoromethyl)pyrimidine-5-carboxylic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(2-(difluoromethyl)pyrimidine-5-carboxamido)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 327) was obtained. (MS (m/z) 514.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.62 - 9.34 (m, 3H), 8.97 (s, 1H), 8.30 - 7.93 (m, 2H), 7.41 (s, 1H), 6.84 (t, J = 54.1 Hz, 1H), 5.99 (d, J = 7.2 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H). Example 84 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 - carboxamido ) pyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 328)
向(R)-(4-(5-胺基吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(中間物10)(0.049 mmol)、1-氰基環丙烷甲酸(0.058 mmol)及(1-氰基-2-乙氧基-2-側氧基亞乙基胺氧基)二甲胺基-N-𠰌啉基-碳正離子六氟磷酸酯(0.058 mmol)於二氯甲烷(0.5 mL)中之混合物中添加N,N-二異丙基乙胺(0.097 mmol)。攪拌反應物48小時,隨後濃縮且藉由逆相HPLC純化,得到(R)-(4-(5-(1-氰基環丙烷-1甲醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯(化合物328)(MS(m/z) 470.0 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.22 (s, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.11 - 7.67 (m, 2H), 5.95 (d, J = 6.8 Hz, 1H), 4.01 (s, 3H), 1.88 - 1.80 (m, 2H), 1.80 - 1.72 (m, 2H), 1.62 (s, 3H)。 實例 85 :製備化合物 286-287 及 329-332 To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 10) (0.049 mmol), 1-cyanocyclopropanecarboxylic acid (0.058 mmol) and (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-N-oxo-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1 The reaction was stirred for 48 hours, then concentrated and purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 328) (MS (m/z) 470.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.22 (s, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.11 - 7.67 (m, 2H), 5.95 (d, J = 6.8 Hz, 1H), 4.01 (s, 3H), 1.88 - 1.80 (m, 2H), 1.80 - 1.72 (m, 2H), 1.62 (s, 3H). Example 85 : Preparation of Compounds 286-287 and 329-332
化合物286-287及329-332一般根據流程C合成。舉例而言,如下製備(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(化合物329)。 製備 (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 ( 化合物 329) 步驟 1 : (R)-(4-(5-(( 三級丁氧基羰基 ) 胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 Compounds 286-287 and 329-332 were generally synthesized according to Scheme C. For example, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 329) was prepared as follows. Preparation of (R)-1- (2 - chloro - 5- fluoropyridin - 3- yl ) ethyl (4-(5-(1- cyanocyclopropane -1- carboxamido ) pyrimidin - 2 - yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Compound 329) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin - 3- yl ) ethyl ester
向4-(5-((三級丁氧基羰基)胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(中間物9)(0.62 mmol)於THF(5 mL)中之混合物中添加T3P(50%於DMF中,0.94 mmol)、TMS-N3 (0.67 mmol)及三乙胺(1.2 mmol)。在70℃下加熱混合物30分鐘。添加(R)-1-(2-氯-5-氟吡啶-3-基)乙-1-醇(0.94 mmol)且在70℃下加熱溶液90分鐘。將反應冷卻至室溫,濃縮且藉由矽膠層析純化,得到(R)-(4-(5-((三級丁氧基羰基)胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯。(MS (m/z ) 493.2 [M+H]+ )。 步驟 2 : (R)-(4-(5- 胺基嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 ( 中間物 11) To a mixture of 4-(5-((tributyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 9) (0.62 mmol) in THF (5 mL) was added T3P (50% in DMF, 0.94 mmol), TMS-N3 (0.67 mmol) and triethylamine (1.2 mmol). The mixture was heated at 70 °C for 30 min. (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (0.94 mmol) was added and the solution was heated at 70 °C for 90 min. The reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-((tributyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5- yl )carbamate. (MS ( m/z ) 493.2 [M+H] + ). Step 2 : (R)-1-(2- chloro -5- fluoropyridin - 3- yl ) ethyl (4-(5- aminopyrimidin - 2-yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Intermediate 11)
將含4 M HCl之1,4-二㗁烷(20 mmol)添加至(R)-(4-(5-((三級丁氧基羰基)胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(0.49 mmol)。將所得懸浮液在室溫下攪拌18小時。反應物經濃縮得到呈鹽酸鹽形式之(R)-(4-(5-胺基嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(中間物11)。(MS (m/z ) 393.1 [M+H]+ )。 步驟 3 : (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 4 M HCl in 1,4-dioxane (20 mmol) was added to (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-((tributyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.49 mmol). The resulting suspension was stirred at room temperature for 18 h. The reactant was concentrated to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 11) as a hydrochloride salt. (MS ( m/z ) 393.1 [M+H] + ). Step 3 : (R)-(4-(5-(1 -cyanocyclopropane -1 -carboxamido ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester
向小瓶中裝入(R)-(4-(5-胺基嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯鹽酸鹽(0.05 mmol)(中間物11)、1-氰基環丙烷-1-甲酸(0.06 mmol), N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.07 mmol)及吡啶(2 mmol)。在室溫下攪拌反應混合物18小時,濃縮且藉由逆相HPLC純化以得到(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯。(MS (m/z ) 486.2 [M+H]+ )。1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.98 (bs, 1H), 8.99 (s, 2H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.82 (bs, 1H), 3.91 (s, 3H), 1.84 - 1.68 (m, 4H), 1.55 (bs, 3H)。A vial was charged with (R)-ethyl (4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 1-(2-chloro-5-fluoropyridin-3-yl) hydrochloride (0.05 mmol) (intermediate 11), 1-cyanocyclopropane-1-carboxylic acid (0.06 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 mmol) and pyridine (2 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS ( m/z ) 486.2 [M+H] + ). 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.98 (bs, 1H), 8.99 (s, 2H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.82 (bs, 1H), 3.91 (s, 3H), 1.84 - 1.68 (m, 4H), 1.55 (bs, 3H).
化合物286-287及329-332(表5)類似地根據流程C,步驟4,藉由使(R)- (4-(5-胺基嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯鹽酸鹽(中間物11)與表4中所列之試劑環而非1-氰基環丙烷-1-甲酸反應來製備。Compounds 286-287 and 329-332 (Table 5) were prepared similarly according to Scheme C, Step 4, by reacting (R)-(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 11) with the reagent rings listed in Table 4 instead of 1-cyanocyclopropane-1-carboxylic acid.
化合物286-287係使用(1S,2S)-1-氰基-2-(二氟甲基)環丙烷-1-甲酸與(1R,2R)-1-氰基-2-(二氟甲基)環丙烷-1-甲酸之混合物來製備,接著進行對掌性SFC純化。表 5 :根據流程 C 製備之化合物。
向4-(5-((第三丁氧基羰基)胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(0.62 mmol)於THF (5 mL)中之混合物中添加T3P(50%於DMF中,0.94 mmol)、TMS-N3(0.69 mmol)及三乙胺(1.2 mmol)。在70℃下加熱混合物30分鐘。添加(R)-1-(2-氯-5-氟吡啶-3-基)乙-1-醇(0.94 mmol)且在70℃下加熱溶液90分鐘。將反應物冷卻至室溫,濃縮且藉由矽膠層析純化,得到(R)-(4-(5-((三級丁氧基羰基)胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯。(MS (m/z ) 492.9. [M+H]+ )。 步驟 2 : (R)-(4-(5- 胺基吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 To a mixture of 4-(5-((tert-butoxycarbonyl)amino)pyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.62 mmol) in THF (5 mL) was added T3P (50% in DMF, 0.94 mmol), TMS-N3 (0.69 mmol) and triethylamine (1.2 mmol). The mixture was heated at 70 °C for 30 min. (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (0.94 mmol) was added and the solution was heated at 70 °C for 90 min. The reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to give (R)-(4-(5-((tributyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester. (MS ( m/z ) 492.9. [M+H] + ). Step 2 : (R)-(4-(5- aminopyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester
將含4 M HCl之1,4-二㗁烷(14 mmol)添加至(R)-(4-(5-((三級丁氧基羰基)胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯(0.34 mmol)。將所得懸浮液在室溫下攪拌18小時。反應物經濃縮得到呈鹽酸鹽形式之(R)-(4-(5-胺基吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯。 步驟 3 : (R)-(4-(5-(3- 氟雙環 [1.1.1] 戊烷 -1- 甲醯胺基 ) 吡 𠯤 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙酯 4 M HCl in 1,4-dioxane (14 mmol) was added to 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (R)-(4-(5-((tributyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.34 mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to give 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt. Step 3 : (R) -1-(2- chloro-5 - fluoropyridin -3- yl ) ethyl (4-(5-(3- fluorobicyclo [1.1.1] pentane - 1 - carboxamido ) pyrrolidone -2- yl ) -1- methyl -1H-1,2,3 - triazol - 5 - yl ) carbamate
向小瓶中裝入(R)-(4-(5-胺基吡嗪-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯鹽酸鹽(0.06 mmol)、 3-氟雙環[1.1.1]戊烷-1-甲酸(0.08 mmol)、N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.12 mmol)及吡啶(2 mmol)。在室溫下攪拌反應混合物18小時,濃縮且藉由逆相HPLC純化以得到(R)-(4-(5-(3-氟雙環[1.1.1]戊烷-1-甲醯胺基)吡𠯤-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2-氯-5-氟吡啶-3-基)乙酯。(MS (m/z ) 505.2 [M+H]+ )。1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.03 (bs, 1H), 9.20 (d, J = 1.6 Hz, 1H), 8.92 (d, J = 1.5 Hz, 1H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.83 (bs, 1H), 3.92 (s, 3H), 2.47 (d, J = 2.5 Hz, 6H), 1.55 (bs, 3H)。 實例 87 : 製備 (R)-(4-(5-((1r,3R)-3- 氰基 -3- 甲氧基環丁烷 -1- 甲醯胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 334) 及 (R)-(4-(5-((1s,3S)-3- 氰基 -3- 甲氧基環丁烷 -1- 甲醯胺基 ) 嘧啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 335) A vial was charged with (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.06 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (0.08 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 mmol), and pyridine (2 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS ( m/z ) 505.2 [M+H] + ). 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.03 (bs, 1H), 9.20 (d, J = 1.6 Hz, 1H), 8.92 (d, J = 1.5 Hz, 1H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.83 (bs, 1H), 3.92 (s, 3H), 2.47 (d, J = 2.5 Hz, 6H), 1.55 (bs, 3H). Example 87 : Preparation of (R)-(4-(5-((1r,3R)-3- cyano -3- methoxycyclobutane -1 - carboxamido ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 334) and (R)-(4-(5-((1s,3S)-3- cyano -3- methoxycyclobutane -1 -carboxamido ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 -yl ) ethyl ester ( Compound 335)
在室溫下將(R)- (4-(5-胺基嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯鹽酸鹽(0.048 mmol)、3-氰基-3-甲氧基環丁烷-1-甲酸(2當量)、EDCI (2當量)於吡啶(1 mL)中之混合物攪拌1小時。反應完成後,藉由製備型HPLC用Gilson製備型HPLC (Gemini管柱,含30%-95% CH3 CN之H2 O與0.1% TFA)純化殘餘物。分離兩個峰;任意指定立體結構。化合物334:(R)-(4-(5-((1r,3R)-3-氰基-3-甲氧基環丁烷-1-甲醯胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z) 514.1 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.06 (s, 2H), 8.07 (m, 1H), 7.98 - 7.69 (m, 1H), 5.96 (m, 1H), 4.02 (s, 3H), 3.46 (s, 2H) 2.99 - 2.79 (m, 2H), 2.76 - 2.48 (m, 2H), 1.63 (s, 3H)。化合物335:(R)-(4-(5-((1s,3S)-3-氰基-3-甲氧基環丁烷-1-甲醯胺基)嘧啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z) 514.1 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 9.05 (s, 2H), 8.05 (s, 1H), 7.97 - 7.75 (m, 1H), 5.96 (m, 1H), 4.01 (s, 3H), 3.55 - 3.49 (m, 1H), 2.85 (m, 2H), 2.66 (m, 2H), 1.63 (s, 3H)。 實例 88 : 製備 (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 336) 步驟 1 : (6- 溴 -5- 氟吡啶 -3- 基 ) 胺基甲酸三級丁酯 A mixture of (R)-(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (0.048 mmol), 3-cyano-3-methoxycyclobutane-1-carboxylic acid (2 equiv.), EDCI (2 equiv.) in pyridine (1 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the residue was purified by preparative HPLC using Gilson preparative HPLC (Gemini column, 30%-95% CH 3 CN in H 2 O and 0.1% TFA). Two peaks were separated; the stereostructure was assigned arbitrarily. Compound 334: (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-cyano-3-methoxycyclobutane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 514.1 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 2H), 8.07 (m, 1H), 7.98 - 7.69 (m, 1H), 5.96 (m, 1H), 4.02 (s, 3H), 3.46 (s, 2H) 2.99 - 2.79 (m, 2H), 2.76 - 2.48 (m, 2H), 1.63 (s, 3H). Compound 335: (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((1s,3S)-3-cyano-3-methoxycyclobutane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 514.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.05 (s, 2H), 8.05 (s, 1H), 7.97 - 7.75 (m, 1H), 5.96 (m, 1H), 4.01 (s, 3H), 3.55 - 3.49 (m, 1H), 2.85 (m, 2H), 2.66 (m, 2H), 1.63 (s, 3H). Example 88 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 336) Step 1 : (6- bromo -5- fluoropyridin -3- yl ) carbamic acid tert-butyl ester
向6-溴-5-氟吡啶-3-胺(2.8 mmol)於THF(20 mL)中之溶液中添加二-二碳酸三級丁酯(5.7 mmol)。將反應物加熱至70℃持續16小時,且經由二氧化矽塞過濾,得到標題化合物,其未經進一步純化即用於下一步驟中。 步驟 2 : 4-(5-(( 三級丁氧基羰基 ) 胺基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 甲酸 To a solution of 6-bromo-5-fluoropyridin-3-amine (2.8 mmol) in THF (20 mL) was added tributyl dicarbonate (5.7 mmol). The reaction was heated to 70 °C for 16 h and filtered through a silica plug to afford the title compound which was used in the next step without further purification. Step 2 : 4-(5-(( tributyloxycarbonyl ) amino )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5-carboxylic acid
在-70℃下向4-溴-1-甲基-1H-1,2,3-三唑-5-甲酸(1.3 mmol)於四氫呋喃(20 mL)中之溶液中添加1 M雙(三甲基矽基)胺基鋰(1.5 mmol)溶液。15分鐘後,添加2.5 M正丁基鋰(2.5 mmol)溶液。1小時後,添加2 M氯化鋅溶液(2.5 mmol),且在15℃下攪拌反應物30分鐘。此時,向反應物中添加(6-溴-5-氟吡啶-3-基)胺基甲酸三級丁酯(1 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(0.08 mmol)且將反應混合物加熱至90℃持續3小時。反應完成後,使反應物冷卻且用1 M氯化氫水溶液(20 mL)稀釋。用乙酸乙酯(30 mL × 3)萃取反應混合物。合併之有機層經硫酸鈉乾燥,濃縮,藉由管柱層析純化,得到4-(5-((三級丁氧基羰基)胺基)-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸。 步驟 3 : (R)-(6-(5-(((1-(2,5- 二氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-5- 氟吡啶 -3- 基 ) 胺基甲酸三級丁酯 To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (1.3 mmol) in tetrahydrofuran (20 mL) was added 1 M solution of lithium bis(trimethylsilyl)amide (1.5 mmol) at -70 °C. After 15 minutes, 2.5 M solution of n-butyl lithium (2.5 mmol) was added. After 1 hour, 2 M solution of zinc chloride (2.5 mmol) was added and the reaction was stirred at 15 °C for 30 minutes. At this point, tributyl (6-bromo-5-fluoropyridin-3-yl)carbamate (1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.08 mmol) were added to the reaction and the reaction mixture was heated to 90 °C for 3 hours. After the reaction was completed, the reactants were cooled and diluted with 1 M aqueous hydrogen chloride solution (20 mL). The reaction mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, concentrated, and purified by column chromatography to obtain 4-(5-((tri-butyloxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 3 : (R)-(6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl )-5- fluoropyridin -3- yl ) carbamic acid tributyl ester
將4-(5-((三級丁氧基羰基)胺基)-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-甲酸(3.1 mmol)、疊氮基三甲基矽烷(4.7 mmol)及T3P(50%於DMF中)(4.7 mmol)溶解於THF(5 mL)中。在室溫下逐滴添加三乙胺(9.4 mmol),在5-30分鐘之後產生澄清溶液。添加(R)-1-(2,5-二氟吡啶-3-基)乙-1-醇(9.4 mmol)且在80℃下加熱反應物2小時。隨後添加矽膠且在真空中濃縮粗混合物,且隨後藉由管柱層析純化,得到(R)-(6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-5-氟吡啶-3-基)胺基甲酸三級丁酯(0.6 mmol)。 步驟 4 : (R)-(4-(5- 胺基 -3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯鹽酸鹽 ( 中間物 12) 4-(5-((tri-butyloxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (3.1 mmol), trimethylsilylazide (4.7 mmol) and T3P (50% in DMF) (4.7 mmol) were dissolved in THF (5 mL). Triethylamine (9.4 mmol) was added dropwise at room temperature to give a clear solution after 5-30 minutes. (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (9.4 mmol) was added and the reaction was heated at 80 °C for 2 hours. Silica gel was then added and the crude mixture was concentrated in vacuo and then purified by column chromatography to give (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fluoropyridin-3-yl)carbamic acid tert-butyl ester (0.6 mmol). Step 4 : (R)-(4-(5- amino -3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester hydrochloride ( Intermediate 12)
使(R)-(6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-5-氟吡啶-3-基)胺基甲酸三級丁酯(0.6 mmol)懸浮於1.6 mL含4 M鹽酸之二㗁烷中1小時。隨後在真空中濃縮混合物,得到(R)-(4-(5-胺基-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5--3-基)乙酯氯化氫鹽(中間物12)且未經進一步純化即使用。 步驟 5 : (R)-(4-(5-(1- 氰基環丙烷 -1- 甲醯胺基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 (R)-tributyl(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fluoropyridin-3-yl)carbamate (0.6 mmol) was suspended in 1.6 mL of 4 M hydrochloric acid in dioxane for 1 h. The mixture was then concentrated in vacuo to give 1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-amino-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 12) and used without further purification. Step 5 : (R)-(4-(5-(1 -cyanocyclopropane -1 -carboxamido )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin - 3- yl ) ethyl ester
向(R)-(4-(5-胺基-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯氯化氫鹽(0.07 mmol)於吡啶(1 mL)中之混合物中添加1-氰基環丙烷-1-甲酸(0.07 mmol)及N-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.08 mmol)。使反應混合物在磁性攪拌下靜置2小時,此時添加水(1 mL),藉由HPLC純化粗混合物以得到(R)-(4-(5-(1-氰基環丙烷-1-甲醯胺基)-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z) 486.986 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.78 - 8.52 (m, 1H), 8.19 - 7.53 (m, 3H), 5.90 (d, J = 6.8 Hz, 1H), 4.02 (s, 3H), 1.91 - 1.35 (m, 7H)。 實例 89 : 製備 (R)-(4-(5-(3- 氰基雙環 [1.1.1] 戊烷 -1- 甲醯胺基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 337) (R)-(4-(5-(3- 氰基雙環 [1.1.1] 戊烷 -1- 甲醯胺基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-amino-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.07 mmol) in pyridine (1 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.07 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 486.986 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.78 - 8.52 (m, 1H), 8.19 - 7.53 (m, 3H), 5.90 (d, J = 6.8 Hz, 1H), 4.02 (s, 3H), 1.91 - 1.35 (m, 7H). Example 89 : Preparation of (R)-(4-(5-(3- cyanobicyclo [1.1.1] pentane -1- carboxamido )-3- fluoropyridin -2 -yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 -yl ) ethyl ester ( Compound 337) (R)-1-( 2,5 -difluoropyridin - 3-yl ) ethyl (4-(5-(3- cyanobicyclo [1.1.1] pentane -1 - carboxamido )-3- fluoropyridin -2 - yl )-1- methyl -1H-1,2,3 - triazol -5 - yl ) carbamate
遵循實例88使用3-氰基雙環[1.1.1]戊烷-1-甲酸(0.07 mmol)而非1-氰基環丙烷-1-甲酸來製備(R)-(4-(5-(3-氰基雙環[1.1.1]戊烷-1-甲醯胺基)-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z) 513.010 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.61 (s, 1H), 8.25 - 7.51 (m, 3H), 5.89 (d, J = 7.0 Hz, 1H), 4.01 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H)。 實例 90 : 製備 (R)-(4-(5-(6- 氯煙醯胺基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸 1-(2,5- 二氟吡啶 -3- 基 ) 乙酯 ( 化合物 338) (R)-1-(2,5- 二氟吡啶 -3- 基 )(4-(5-(6- 氯煙醯胺基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸乙酯 Example 88 was followed using 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid (0.07 mmol) instead of 1-cyanocyclopropane-1-carboxylic acid to prepare (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid amido)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 513.010 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.61 (s, 1H), 8.25 - 7.51 (m, 3H), 5.89 (d, J = 7.0 Hz, 1H), 4.01 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H). Example 90 : Preparation of (R)-(4-(5-(6- chloronitroamino )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 338) (R)-1-(2,5 -difluoropyridin -3 -yl )(4-(5-(6- chloronicotinamide )-3 - fluoropyridin -2 - yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate
遵循實例88使用6-氯菸鹼酸(0.07 mmol)而非1-氰基環丙烷-1-甲酸來製備(R)-(4-(5-(6-氯-菸鹼醯胺基)-3-氟吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺基甲酸1-(2,5-二氟吡啶-3-基)乙酯。(MS (m/z) 532.975 [M+H]+)。1H NMR (400 MHz, 甲醇-d4) δ 8.98 (dd, J = 2.5, 0.7 Hz, 1H), 8.73 (s, 1H), 8.38 (dd, J = 8.4, 2.5 Hz, 1H), 8.27 (dd, J = 12.4, 2.1 Hz, 1H), 7.96 (d, J = 78.6 Hz, 2H), 7.66 (dd, J = 8.3, 0.8 Hz, 1H), 5.91 (d, J = 6.8 Hz, 1H), 4.03 (s, 3H), 1.62 (s, 3H)。 實例 91 : 製備外消旋 -(1R,2R)-1- 氰基 -2-( 二氟甲基 ) 環丙烷 -1- 甲酸 步驟 1 : (3,3- 二氟烯丙基 )( 苯基 ) 硫烷 Example 88 was followed using 6-chloronicotinic acid (0.07 mmol) instead of 1-cyanocyclopropane-1-carboxylic acid to prepare (R)-(4-(5-(6-chloro-nicotinamido)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester. (MS (m/z) 532.975 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.98 (dd, J = 2.5, 0.7 Hz, 1H), 8.73 (s, 1H), 8.38 (dd, J = 8.4, 2.5 Hz, 1H), 8.27 (dd, J = 12.4, 2.1 Hz, 1H), 7.96 (d, J = 78.6 Hz, 2H), 7.66 (dd, J = 8.3, 0.8 Hz, 1H), 5.91 (d, J = 6.8 Hz, 1H), 4.03 (s, 3H), 1.62 (s, 3H). Example 91 : Preparation of rac- (1R,2R)-1- cyano -2-( difluoromethyl ) cyclopropane -1- carboxylic acid Step 1 : (3,3 -difluoroallyl )( phenyl ) sulfane
在N2 下將NaH (153 mmol)添加至250 mL瓶中。添加正己烷(50.0 mL)且在25℃下攪拌5分鐘。藉由注射器除去正己烷。在0℃下向反應物中添加二㗁烷(120 mL)。將PhSH (118 mmol)添加至混合物中,且在0℃下攪拌0.5小時。在0℃下將3-溴-3,3-二氟丙-1-烯(177 mmol)添加至混合物中。使反應物升溫至25℃且在25℃下攪拌1小時。在0℃下用飽和NH4 Cl (50.0 mL)淬滅反應物,且用乙酸乙酯(100 mL * 4)萃取。將有機相用鹽水(100 mL)洗滌且經無水Na2 SO4 乾燥。過濾溶液且於真空中濃縮。殘餘物係藉由管柱層析純化以得到(3,3-二氟烯丙基)(苯基)硫烷。 步驟 2 : (E)-(3,3- 二氟丙 -1- 烯 -1- 基 )( 苯基 ) 硫烷 NaH (153 mmol) was added to a 250 mL bottle under N2 . n-Hexane (50.0 mL) was added and stirred at 25°C for 5 minutes. n-Hexane was removed by syringe. Dioxane (120 mL) was added to the reaction at 0°C. PhSH (118 mmol) was added to the mixture and stirred at 0°C for 0.5 hours. 3-Bromo-3,3-difluoroprop-1-ene (177 mmol) was added to the mixture at 0°C. The reaction was warmed to 25°C and stirred at 25°C for 1 hour. The reaction was quenched with saturated NH4Cl (50.0 mL) at 0°C and extracted with ethyl acetate (100 mL * 4). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4 . The solution was filtered and concentrated in vacuo. The residue was purified by column chromatography to give (3,3-difluoroallyl)(phenyl)sulfane. Step 2 : (E)-(3,3 -difluoroprop -1- en -1- yl )( phenyl ) sulfane
將(3,3-二氟烯丙基)(苯基)硫烷(53.7 mmol)溶解於100 mL瓶中之DMSO (20.0 mL)中。在10℃下將t-BuOK (2.68 mmol)添加至混合物中。使混合物升溫至25℃且在25℃下攪拌1小時。在0-10℃下藉由添加H2 O (200 mL)淬滅反應物。向混合物中添加正己烷(100 mL),且用正己烷(200 mL * 5)萃取反應物。用鹽水(100 mL)洗滌合併之有機相,且經無水Na2 SO4 乾燥。過濾且在真空下濃縮以得到(E)-(3,3-二氟丙-1-烯-1-基)(苯基)硫烷。 步驟 3 : (E)-(3,3- 二氟丙 -1- 烯 -1- 基 ) 三氟甲磺酸二苯基鋶 (3,3-Difluoroallyl)(phenyl)sulfane (53.7 mmol) was dissolved in DMSO (20.0 mL) in a 100 mL bottle. t-BuOK (2.68 mmol) was added to the mixture at 10°C. The mixture was warmed to 25°C and stirred at 25°C for 1 hour. The reaction was quenched by adding H 2 O (200 mL) at 0-10°C. n-Hexane (100 mL) was added to the mixture, and the reaction was extracted with n-hexane (200 mL * 5). The combined organic phases were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4. Filtered and concentrated under vacuum to give (E)-(3,3-difluoroprop-1-en-1-yl)(phenyl)sulfane. Step 3 : (E)-(3,3 -difluoroprop- 1- en -1 -yl ) diphenyltrifluoromethanesulfonate
將三氟甲烷磺酸二苯基碘(48.8 mmol)添加至250 mL瓶中,且添加DCE (60.0 mL)。添加(E)-(3,3-二氟丙-1-烯-1-基)(苯基)硫烷(51.3 mmol),接著在10℃下將Cu粉末(244 mmol)添加至瓶中。將反應物在10-25℃下攪拌0.5小時,隨後浸沒於預加熱油浴(80℃)中,且攪拌2小時。將反應物冷卻至20℃且隨後經由矽藻土墊過濾且用DCM (80 mL * 4)洗滌。濃縮濾液且藉由管柱層析(SiO2,DCM/丙酮=100/1至20/1,Rf=0.50)純化,獲得(E)-(3,3-二氟丙-1-烯-1-基)三氟甲磺酸二苯基鋶。 步驟 4 : 外消旋 -2-(1R,2R)-1- 氰基 -2-( 二氟甲基 ) 環丙烷 -1- 甲酸乙氧基乙酯 Diphenyliodonium trifluoromethanesulfonate (48.8 mmol) was added to a 250 mL bottle, and DCE (60.0 mL) was added. (E)-(3,3-difluoroprop-1-en-1-yl)(phenyl)sulfane (51.3 mmol) was added, followed by Cu powder (244 mmol) at 10°C. The reaction was stirred at 10-25°C for 0.5 hours, then immersed in a preheated oil bath (80°C), and stirred for 2 hours. The reaction was cooled to 20°C and then filtered through a celite pad and washed with DCM (80 mL * 4). The filtrate was concentrated and purified by column chromatography (SiO2, DCM/acetone = 100/1 to 20/1, Rf = 0.50) to obtain (E)-(3,3-difluoroprop-1-en-1-yl)trifluoromethanesulfonate diphenylphosphine. Step 4 : 2-(1R,2R)-1- cyano -2-( difluoromethyl ) cyclopropane -1- carboxylic acid ethoxyethyl ester
在25℃下將2-乙氧基乙基2-氰基乙酸酯(63.6 mmol)於丙酮(100 mL)添加至250 mL瓶中。添加K2 CO3 (191 mmol),接著在25℃下將(E)-(3,3-二氟丙-1-烯-1-基)三氟甲磺酸二苯基鋶(70.0 mmol)添加至瓶中且攪拌1小時。反應物經由矽藻土墊過濾且用DCM (100 ml * 3)洗滌。在真空下濃縮有機相,且藉由HPLC(管柱:Phenomenex luna C18 (250*70 mm,15 μm);移動相:[水(0.1% TFA)-ACN];B%:25ACN%-55ACN%,25 min)純化。產物溶離份用飽和NaHCO3 調節至pH=6-7。在減壓下濃縮溶離份以除去ACN,隨後用乙酸乙酯(200 mL * 3)萃取,且經無水Na2 SO4 乾燥。過濾且在真空下濃縮,得到粗產物,其藉由製備型HPLC(管柱:Welch Ultimate XB-CN 250*70*10 μm;移動相:[己烷-EtOH(0.1% NH3 .H2 O)];B%: 1%-40%,15 min)進一步純化且濃縮,獲得外消旋-2-(1R,2R)-1-氰基-2-(二氟甲基)環丙烷-1-甲酸乙氧基乙酯。 步驟 5 : 外消旋 -(1R,2R)-1- 氰基 -2-( 二氟甲基 ) 環丙烷 -1- 甲酸 2-Ethoxyethyl 2-cyanoacetate (63.6 mmol) was added to a 250 mL bottle in acetone (100 mL) at 25°C. K 2 CO 3 (191 mmol) was added, followed by (E)-(3,3-difluoroprop-1-en-1-yl)trifluoromethanesulfonate (70.0 mmol) at 25°C and stirred for 1 hour. The reaction was filtered through a diatomaceous earth pad and washed with DCM (100 ml * 3). The organic phase was concentrated under vacuum and purified by HPLC (column: Phenomenex luna C18 (250*70 mm, 15 μm); mobile phase: [water (0.1% TFA)-ACN]; B%: 25ACN%-55ACN%, 25 min). The product fraction was adjusted to pH = 6-7 with saturated NaHCO 3. The fraction was concentrated under reduced pressure to remove ACN, then extracted with ethyl acetate (200 mL * 3), and dried over anhydrous Na 2 SO 4. Filtered and concentrated under vacuum to obtain a crude product, which was further purified and concentrated by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH 3 .H 2 O)]; B%: 1%-40%, 15 min) to obtain racemic-2-(1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid ethoxyethyl ester. Step 5 : Racemic- (1R,2R)-1- cyano -2-( difluoromethyl ) cyclopropane -1- carboxylic acid
將外消旋-2-(1R,2R)-1-氰基-2-(二氟甲基)環丙烷-1-甲酸乙氧基乙酯(34.3 mmol)添加至100 mL瓶中且懸浮於THF(70.0 mL)中。在10℃下將LiOH.H2 O (2 M,34.30 mL)添加至混合物,且在10-25℃下攪拌3小時。用HCl (1 N)將pH調節至2。用乙酸乙酯(50.0 mL * 6)萃取反應物,且用鹽水(50.0 mL)洗滌。有機物經Na2 SO4 乾燥,過濾且在真空下濃縮。用DCM (20.0 mL)濕磨產物且藉由真空過濾收集沈澱物,得到外消旋-(1R,2R)-1-氰基-2-(二氟甲基)環丙烷-1-甲酸。 實例 92 :製備外消旋 -(1S,2S)-1- 氰基 -2- 氟代環丙烷 -1- 甲酸 步驟 1 : 三甲基 (( 苯硫基 ) 乙炔基 ) 矽 烷 Racemic-2-(1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid ethoxyethyl ester (34.3 mmol) was added to a 100 mL bottle and suspended in THF (70.0 mL). LiOH.H 2 O (2 M, 34.30 mL) was added to the mixture at 10° C. and stirred at 10-25° C. for 3 hours. The pH was adjusted to 2 with HCl (1 N). The reactant was extracted with ethyl acetate (50.0 mL * 6) and washed with brine (50.0 mL). The organics were dried over Na 2 SO 4 , filtered and concentrated under vacuum. The product was triturated with DCM (20.0 mL) and the precipitate was collected by vacuum filtration to give rac-(1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid. Example 92 : Preparation of rac- (1S,2S)-1- cyano -2- fluorocyclopropane -1- carboxylic acid Step 1 : Trimethyl ( ( phenylthio ) ethynyl ) silane
在-78℃下將含乙炔基三甲基矽烷(1.43 mol)之THF(1000 mL)逐滴添加至nBuLi(2.5 M,570 mL,1.43 mol)。在-78℃下攪拌反應物30分鐘,且隨後在-78℃下逐滴添加1,2-二苯基二硫烷(1.43 mol)於THF (400 mL)中之溶液。在-78℃下攪拌30分鐘之後,使反應物升溫至15℃且攪拌5小時。將反應物冷卻至0℃且在0℃下逐滴添加H2 O (500 mL)。用EtOAc(500 mL *2)萃取反應物,且將水層傾入NaClO中。將合併之有機層用0.1 M NaOH (500 mL *3)、H2 O (500 mL)洗滌,經Na2 SO4 乾燥,過濾且在真空中濃縮。殘餘物不經純化即直接用於下一步驟中,得到三甲基((苯硫基)乙炔基)矽烷。 步驟 2 : 乙炔基 ( 苯基 ) 硫烷 Ethylenetrimethylsilane (1.43 mol) in THF (1000 mL) was added dropwise to nBuLi (2.5 M, 570 mL, 1.43 mol) at -78°C. The reaction was stirred at -78°C for 30 minutes, and then a solution of 1,2-diphenyldisulfane (1.43 mol) in THF (400 mL) was added dropwise at -78°C. After stirring at -78°C for 30 minutes, the reaction was warmed to 15°C and stirred for 5 hours. The reaction was cooled to 0°C and H 2 O (500 mL) was added dropwise at 0°C. The reaction was extracted with EtOAc (500 mL *2), and the aqueous layer was poured into NaClO. The combined organic layers were washed with 0.1 M NaOH (500 mL *3), H 2 O (500 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was used directly in the next step without purification to obtain trimethyl((phenylthio)ethynyl)silane. Step 2 : Ethynyl ( phenyl ) sulfane
將三甲基((苯硫基)乙炔基)矽烷(1.28 mol)添加至MeOH (2000 mL)中。在15℃下逐滴添加K2 CO3 (2.56 mol)於H2 O(600 mL)中之混合物,且攪拌16小時。在濃縮以除去MeOH之後,添加EtOAc (400 mL)及H2 O (200 mL)。分離且用EtOAc (200 mL *2)萃取水層。合併之有機層經Na2 SO4 乾燥,過濾且在真空中濃縮。殘餘物係藉由管柱層析純化,獲得乙炔基(苯基)硫烷。 步驟 3 : (1- 氟乙烯基 )( 苯基 ) 硫烷 Trimethyl((phenylthio)ethynyl)silane (1.28 mol) was added to MeOH (2000 mL). A mixture of K 2 CO 3 (2.56 mol) in H 2 O (600 mL) was added dropwise at 15° C. and stirred for 16 hours. After concentration to remove MeOH, EtOAc (400 mL) and H 2 O (200 mL) were added. The aqueous layer was separated and extracted with EtOAc (200 mL *2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain ethynyl(phenyl)sulfane. Step 3 : (1- fluorovinyl )( phenyl ) sulfane
將乙炔基(苯基)硫烷(1.16 mol),Pyr.(3.31 mol)添加至DCM (1000 mL)中。 在0℃下添加HF/Pyr.(4.62 mol),且隨後使反應物升溫至15℃且攪拌10分鐘。緩慢添加飽和NaHCO3 及NaHCO3 固體以調節pH=8。將有機層分離,用鹽水(1000 mL)洗滌,經Na2 SO4 乾燥,過濾且在真空中濃縮。殘餘物係藉由管柱層析純化以得到(1-氟乙烯基)(苯基)硫烷。 步驟 4 : (1- 氟乙烯基 ) 三氟甲磺酸二苯基鋶 Ethynyl(phenyl)sulfane (1.16 mol), Pyr. (3.31 mol) were added to DCM (1000 mL). HF/Pyr. (4.62 mol) was added at 0°C, and then the reaction was warmed to 15°C and stirred for 10 minutes. Saturated NaHCO 3 and NaHCO 3 solid were slowly added to adjust pH=8. The organic layer was separated, washed with brine (1000 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography to give (1-fluorovinyl)(phenyl)sulfane. Step 4 : (1- fluorovinyl ) diphenylphosphine trifluoromethanesulfonate
將(1-氟乙烯基)(苯基)硫烷(272 mmol)懸浮於DCE (400 mL)中。在15℃下添加三氟烷磺酸二苯基碘(258 mmol)及Cu(1.36 mol)。將反應物加熱至100℃且攪拌30分鐘。將反應物冷卻至15℃,過濾且用DCM (100 mL)洗滌濾餅。在真空中濃縮濾液,且藉由管柱層析純化殘餘物以得到(1-氟乙烯基)三氟甲磺酸二苯基鋶。 步驟 5 : 外消旋 -(1S,2S)-1- 氰基 -2- 氟代環丙烷 -1- 甲酸乙酯 (1-Fluorovinyl)(phenyl)sulfane (272 mmol) was suspended in DCE (400 mL). Diphenyliodonium triflate (258 mmol) and Cu (1.36 mol) were added at 15 °C. The reaction was heated to 100 °C and stirred for 30 minutes. The reaction was cooled to 15 °C, filtered and the filter cake was washed with DCM (100 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give diphenylstennium (1-fluorovinyl)triflate. Step 5 : rac- (1S,2S)-1- cyano -2- fluorocyclopropane -1- carboxylic acid ethyl ester
將2-氰基乙酸乙酯(78.8 mmol)添加至MeCN (180 mL)中。在15℃下添加DBU(94.6 mmol)且攪拌10分鐘,接著在15℃下逐份添加(1-氟乙烯基)三氟甲磺酸二苯基鋶(78.8 mmol)。在15℃下攪拌30分鐘後,藉由添加飽和NH4 Cl (50 mL)淬滅反應物。用乙酸乙酯(100 mL)萃取混合物兩次且合併之有機層經Na2 SO4 乾燥,過濾且在真空中濃縮。藉由管柱層析純化殘餘物以得到外消旋-(1S,2S)-1-氰基-2-氟代環丙烷-1-甲酸乙酯 步驟 6 : 外消旋 -(1S,2S)-1- 氰基 -2- 氟代環丙烷 -1- 甲酸 Ethyl 2-cyanoacetate (78.8 mmol) was added to MeCN (180 mL). DBU (94.6 mmol) was added at 15 °C and stirred for 10 min, followed by the addition of (1-fluorovinyl)diphenylphosphine trifluoromethanesulfonate (78.8 mmol) portionwise at 15 °C. After stirring at 15 °C for 30 min, the reaction was quenched by the addition of saturated NH 4 Cl (50 mL). The mixture was extracted twice with ethyl acetate (100 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain rac-(1S,2S)-1-cyano-2-fluorocyclopropane-1-carboxylic acid ethyl ester. Step 6 : rac- (1S,2S)-1- cyano -2- fluorocyclopropane -1- carboxylic acid ethyl ester
將外消旋-(1S,2S)-1-氰基-2-氟代環丙烷-1-甲酸乙酯(14.0 mmol)懸浮於MeCN (11.0 mL)及H2 O (2.00 mL)中。在15℃下添加三氮雜雙環癸烯(29.4 mmol)且攪拌1小時。用DCM (20 mL)萃取反應物,且藉由HCl (4 M)將水層之pH調節至1-3。用EtOAc (20 mL *3)萃取水層。合併之有機層經Na2 SO4 乾燥,過濾且在真空中濃縮。殘餘物係藉由管柱層析純化以得到外消旋-(1S,2S)-1-氰基-2-氟代環丙烷-1-甲酸。 實例 93 :鈣分析 Racemic-(1S,2S)-1-cyano-2-fluorocyclopropane-1-carboxylic acid ethyl ester (14.0 mmol) was suspended in MeCN (11.0 mL) and H 2 O (2.00 mL). Triazabicyclodecene (29.4 mmol) was added at 15°C and stirred for 1 hour. The reactant was extracted with DCM (20 mL), and the pH of the aqueous layer was adjusted to 1-3 by HCl (4 M). The aqueous layer was extracted with EtOAc (20 mL *3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography to give racemic-(1S,2S)-1-cyano-2-fluorocyclopropane-1-carboxylic acid. Example 93 : Calcium Analysis
在胞內鈣移動分析中量測活體外LPAR1活性。In vitro LPAR1 activity was measured in an intracellular calcium mobilization assay.
將表現人類LPAR1(NM_001401.3)之CHO-K1 EDG2細胞(DiscoverX目錄號# 93-0644C2)接種於總容積為25 μL的達爾伯克改良(Dulbecco's Modification)之伊格爾(Eagle's)培養基(DMEM)中,其中10%胎牛血清、1x PenStrepGlutamine、300 μg /ml潮黴素及800 μg /ml G418以15,000個細胞/孔添加至384孔組織培養盤(Grenier # 781091)中且在37℃下培育隔夜。在測試之前,在37℃下將漢克氏平衡鹽溶液(康寧# 21-023-CV)、20 mM HEPES (康寧# 25-060-CI)、0.1%牛血清白蛋白(西格瑪-奧德里奇# A7906-500G)中之25 μL載鈣染料組分A (FLIPR鈣6分析試劑盒分子裝置# R8190)及2.5 mM 丙磺舒(英傑(Invitrogen) # P36400,新鮮製備)添加至細胞持續60分鐘。CHO-K1 EDG2 cells (DiscoverX catalog # 93-0644C2) expressing human LPAR1 (NM_001401.3) were seeded in a total volume of 25 μL of Dulbecco's Modification of Eagle's Medium (DMEM) with 10% fetal bovine serum, 1x PenStrepGlutamine, 300 μg/ml hygromycin and 800 μg/ml G418 at 15,000 cells/well in 384-well tissue culture plates (Grenier # 781091) and incubated overnight at 37°C. Prior to the assay, 25 μL of calcium loading dye component A (FLIPR Calcium 6 Assay Kit Molecular Devices #R8190) and 2.5 mM probenecid (Invitrogen #P36400, prepared fresh) in Hank's balanced salt solution (Corning #21-023-CV), 20 mM HEPES (Corning #25-060-CI), 0.1% bovine serum albumin (Sigma-Aldrich #A7906-500G) were added to the cells for 60 min at 37°C.
記錄LPA 18:2之促效劑劑量曲線(Avanti極性脂質目錄號#857138,0.5 nM至10 μM)以測定用於後續拮抗劑分析之LPA 18:2 EC80 。對於促效劑劑量曲線,在染料裝載之後2小時自培育箱移出細胞且轉移至FLIPR Tetra儀器(分子裝置,聖荷西(San Jose),CA)。監測鈣移動5分鐘且將含10 μL 6X LPA之HBSS/20 mM Hepes/0.1%牛血清白蛋白(BSA)添加至分析中的細胞中5秒。Agonist dosing curves for LPA 18:2 (Avanti Polar Lipids Catalog #857138, 0.5 nM to 10 μM) were recorded to determine the LPA 18:2 EC80 for subsequent antagonist analysis. For agonist dosing curves, cells were removed from the incubator 2 hours after dye loading and transferred to a FLIPR Tetra instrument (Molecular Devices, San Jose, CA). Calcium mobilization was monitored for 5 minutes and 10 μL of 6X LPA in HBSS/20 mM Hepes/0.1% bovine serum albumin (BSA) was added to the cells under analysis for 5 seconds.
為測定測試化合物之LPAR1拮抗劑活性,細胞與測試化合物以0.5 nM至10 μM之劑量範圍預培育,接著為EC80 濃度(100 nM)之LPA。在染料裝載之後,自培育箱移出細胞且添加0.3 μL 200X拮抗劑。細胞在37℃下培育60分鐘。在FLIPR Tetra上量測拮抗劑活性。監測鈣移動3.5分鐘且將含10 μL 6X EC80 LPA之HBSS、20 mM HEPES及0.1% BSA添加至分析中的細胞中5秒。使用劑量反應工具(吉利德科學公司(Gilead Sciences Inc.))針對拮抗劑濃度log10 繪製信號振幅(最大值減去最小值)值以測定EC50 。To determine the LPAR1 antagonist activity of test compounds, cells were pre-incubated with test compounds at doses ranging from 0.5 nM to 10 μM, followed by LPA at the EC 80 concentration (100 nM). After dye loading, cells were removed from the incubator and 0.3 μL of 200X antagonist was added. Cells were incubated at 37°C for 60 minutes. Antagonist activity was measured on the FLIPR Tetra. Calcium mobilization was monitored for 3.5 minutes and 10 μL of 6X EC 80 LPA in HBSS, 20 mM HEPES, and 0.1% BSA was added to the cells under analysis for 5 seconds. EC50 values were determined by plotting signal amplitude (maximum minus minimum) against log10 of antagonist concentration using the dose response tool (Gilead Sciences Inc.).
為分析例示化合物之拮抗潛力,在LPAR1鈣移動分析中測定化合物1至338之EC50
值。結果展示於表6 (LPAR1 EC50
)中。化合物編號對應於實例1至92中之化合物編號。N/A=不可用。 表 6
除非另外定義,否則本文所使用之所有技術及科學術語均具有與本發明所屬領域中之普通技術人員通常所理解之含義相同之含義。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
因此,應理解,儘管已藉由較佳實施例及視情況存在之特徵特定地揭示本發明,但本文中所揭示之實施於本文中之本發明的修改、改進及變化可由熟習此項技術者採用,且認為此類修飾、改進及變化在本發明之範疇內。此處提供之材料、方法及實例表示較佳實施例、為例示性的,且不意欲作為對本發明之範疇的限制。Therefore, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optionally existing features, modifications, improvements and variations of the present invention disclosed herein and implemented herein may be adopted by those skilled in the art, and such modifications, improvements and variations are considered to be within the scope of the present invention. The materials, methods and examples provided herein represent preferred embodiments, are exemplary, and are not intended to be limiting of the scope of the present invention.
已在本文中廣泛地且一般性地描述本發明。屬於通用揭示內容內的較狹義物種及亞屬組中之每一者亦形成本發明之一部分。此包括本發明之通用描述,其限制條件或負面限制為自該類屬中除去任何標的物,無論所刪除之材料是否在本文中特定敍述。The invention has been described broadly and generally herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form a part of the invention. This includes the generic description of the invention with a limitation or negative limitation of removing any subject matter from that genus, regardless of whether the removed material is specifically described herein.
此外,若本發明之特徵或態樣關於馬庫什(Markush)群組描述,則熟習此項技術者將認識到本發明亦籍此關於馬庫什群組之任何個別成員或成員之子組描述。In addition, if features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.
應理解,儘管已結合以上實施例描述本發明,前述描述及實例意圖說明且不限制本發明之範疇。本發明範疇內之其他態樣、優點及修改將為熟習本發明相關技術者顯而易見。It should be understood that although the present invention has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the present invention. Other aspects, advantages and modifications within the scope of the present invention will be apparent to those skilled in the art.
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